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1. Overexpression of Egr1 Transcription Regulator Contributes to Schwann Cell Differentiation Defects in Neural Crest-Specific Adar1 Knockout Mice

Author: Lisa Zerad, Nadjet Gacem, Fanny Gayda, Lucie Day, Ketty Sinigaglia, Laurence Richard, Melanie Parisot, Nicolas Cagnard, Stephane Mathis, Christine Bole-Feysot, Mary A. O’Connell, Veronique Pingault, Emilie Dambroise, Liam P. Keegan, Jean Michel Vallat, and Nadege Bondurand
Subjects: Schwann cells, differentiation, ADAR1, MAVS, EGR1, neural crest, Cytology, QH573-671
Abstract: Adenosine deaminase acting on RNA 1 (ADAR1) is the principal enzyme for the adenosine-to-inosine RNA editing that prevents the aberrant activation of cytosolic nucleic acid sensors by endogenous double stranded RNAs and the activation of interferon-stimulated genes. In mice, the conditional neural crest deletion of Adar1 reduces the survival of melanocytes and alters the differentiation of Schwann cells that fail to myelinate nerve fibers in the peripheral nervous system. These myelination defects are partially rescued upon the concomitant removal of the Mda5 antiviral dsRNA sensor in vitro, suggesting implication of the Mda5/Mavs pathway and downstream effectors in the genesis of Adar1 mutant phenotypes. By analyzing RNA-Seq data from the sciatic nerves of mouse pups after conditional neural crest deletion of Adar1 (Adar1cKO), we here identified the transcription factors deregulated in Adar1cKO mutants compared to the controls. Through Adar1;Mavs and Adar1cKO;Egr1 double-mutant mouse rescue analyses, we then highlighted that the aberrant activation of the Mavs adapter protein and overexpression of the early growth response 1 (EGR1) transcription factor contribute to the Adar1 deletion associated defects in Schwann cell development in vivo. In silico and in vitro gene regulation studies additionally suggested that EGR1 might mediate this inhibitory effect through the aberrant regulation of EGR2-regulated myelin genes. We thus demonstrate the role of the Mda5/Mavs pathway, but also that of the Schwann cell transcription factors in Adar1-associated peripheral myelination defects.
Published: 2024
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2. A non-coding variant in the Kozak sequence of RARS2 strongly decreases protein levels and causes pontocerebellar hypoplasia

Author: Romain Nicolle, Nami Altin, Karine Siquier-Pernet, Sherlina Salignac, Pierre Blanc, Arnold Munnich, Christine Bole-Feysot, Valérie Malan, Barthélémy Caron, Patrick Nitschké, Isabelle Desguerre, Nathalie Boddaert, Marlène Rio, Antonio Rausell, and Vincent Cantagrel
Subjects: Pontocerebellar Hypoplasia, RARS2, Kozak, Non-coding variant, Bioinformatic predictions, Internal medicine, RC31-1245, Genetics, QH426-470
Abstract: Abstract Bi-allelic variants in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene have been involved in early-onset encephalopathies classified as pontocerebellar hypoplasia (PCH) type 6 and in epileptic encephalopathy. A variant (NM_020320.3:c.-2A > G) in the promoter and 5’UTR of the RARS2 gene has been previously identified in a family with PCH. Only a mild impact of this variant on the mRNA level has been detected. As RARS2 is non-dosage-sensitive, this observation is not conclusive in regard of the pathogenicity of the variant. We report and describe here a new patient with the same variant in the RARS2 gene, at the homozygous state. This patient presents with a clinical phenotype consistent with PCH6 although in the absence of lactic acidosis. In agreement with the previous study, we measured RARS2 mRNA levels in patient’s fibroblasts and detected a partially preserved gene expression compared to control. Importantly, this variant is located in the Kozak sequence that controls translation initiation. Therefore, we investigated the impact on protein translation using a bioinformatic approach and western blotting. We show here that this variant, additionally to its effect on the transcription, also disrupts the consensus Kozak sequence, and has a major impact on RARS2 protein translation. Through the identification of this additional case and the characterization of the molecular consequences, we clarified the involvement of this Kozak variant in PCH and on protein synthesis. This work also points to the current limitation in the pathogenicity prediction of variants located in the translation initiation region.
Published: 2023
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3. HOMOZYGOUS CBL MUTATION IN B LYMPHOCYTES AFTER CBL-DRIVEN JMML IMPAIRS B CELL MATURATION, FUNCTION AND ANTIBACTERIAL IMMUNITY

Author: Jonathan Bohlen, Marine Michelet, Federica Barzaghi, Francesco Saettini, Francesca Vendemini, Albert Catala, Laia Alsina, Francesca Conti, Fillippo Consonni, Davide Learndini, Riccardo Masetti, Edoardo Muratore, Francesco Baccelli, Ivan Bagaric, Taja Vatovec, Feroj Seyed, Isabelle Andre, Lori Buetow, Eric Delabesse, Laetitia Largeaud, Cindy Ma, Laurent Abel, Steicy Sobrino, Masato Ogishi, Boris Bessot, Cecile Rouillon, Christine Bole, Yoann Seeleuthner, Tom Le Voyer, Darawan Rinchai, Jeremie Rosain, Peng Zhang, Matthieu Chaldebas, Anna-Lena Neehus, Lucia Erazo, Zarah Janda, Camille Soudee, Chantal Lagrese, Emmanuelle Six, Danny Huang, Stuart Tangye, Vivien Beziat, Eleonora Gambineri, Marinella Veltroni, Miriam Erlacher, Alessandro Aiuti, Marlene Pasquet, Jean-Laurent Casanova, and Jacinta Bustamante
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published: 2023
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4. Bi-allelic variations in CRB2, encoding the crumbs cell polarity complex component 2, lead to non-communicating hydrocephalus due to atresia of the aqueduct of sylvius and central canal of the medulla

Author: Aude Tessier, Nathalie Roux, Lucile Boutaud, Elodie Lunel, Leila Hakkakian, Mélanie Parisot, Meriem Garfa-Traoré, Amale Ichkou, Nadia Elkhartoufi, Christine Bole, Patrick Nitschke, Jeanne Amiel, Jelena Martinovic, Férechté Encha-Razavi, Tania Attié-Bitach, and Sophie Thomas
Subjects: Congenital hydrocephalus, Ventriculomegaly, Aqueduct of sylvius atresia, Central canal of the medulla, CRB2, Cell–cell junction, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Congenital hydrocephalus is a common condition caused by the accumulation of cerebrospinal fluid in the ventricular system. Four major genes are currently known to be causally involved in hydrocephalus, either isolated or as a common clinical feature: L1CAM, AP1S2, MPDZ and CCDC88C. Here, we report 3 cases from 2 families with congenital hydrocephalus due to bi-allelic variations in CRB2, a gene previously reported to cause nephrotic syndrome, variably associated with hydrocephalus. While 2 cases presented with renal cysts, one case presented with isolated hydrocephalus. Neurohistopathological analysis allowed us to demonstrate that, contrary to what was previously proposed, the pathological mechanisms underlying hydrocephalus secondary to CRB2 variations are not due to stenosis but to atresia of both Sylvius Aqueduct and central medullar canal. While CRB2 has been largely shown crucial for apico-basal polarity, immunolabelling experiments in our fetal cases showed normal localization and level of PAR complex components (PKCι and PKCζ) as well as of tight (ZO-1) and adherens (β-catenin and N-Cadherin) junction molecules indicating a priori normal apicobasal polarity and cell–cell adhesion of the ventricular epithelium suggesting another pathological mechanism. Interestingly, atresia but not stenosis of Sylvius aqueduct was also described in cases with variations in MPDZ and CCDC88C encoding proteins previously linked functionally to the Crumbs (CRB) polarity complex, and all 3 being more recently involved in apical constriction, a process crucial for the formation of the central medullar canal. Overall, our findings argue for a common mechanism of CRB2, MPDZ and CCDC88C variations that might lead to abnormal apical constriction of the ventricular cells of the neural tube that will form the ependymal cells lining the definitive central canal of the medulla. Our study thus highlights that hydrocephalus related to CRB2, MPDZ and CCDC88C constitutes a separate pathogenic group of congenital non-communicating hydrocephalus with atresia of both Sylvius aqueduct and central canal of the medulla.
Published: 2023
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5. Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function

Author: Mathilda Bedin, Olivia Boyer, Aude Servais, Yong Li, Laure Villoing-Gaudé, Marie-Josephe Tête, Alexandra Cambier, Julien Hogan, Veronique Baudouin, Saoussen Krid, Albert Bensman, Florie Lammens, Ferielle Louillet, Bruno Ranchin, Cecile Vigneau, Iseline Bouteau, Corinne Isnard-Bagnis, Christoph J. Mache, Tobias Schäfer, Lars Pape, Markus Gödel, Tobias B. Huber, Marcus Benz, Günter Klaus, Matthias Hansen, Kay Latta, Olivier Gribouval, Vincent Morinière, Carole Tournant, Maik Grohmann, Elisa Kuhn, Timo Wagner, Christine Bole-Feysot, Fabienne Jabot-Hanin, Patrick Nitschké, Tarunveer S. Ahluwalia, Anna Köttgen, Christian Brix Folsted Andersen, Carsten Bergmann, Corinne Antignac, and Matias Simons
Subjects: Medicine
Published: 2022
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6. MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia

Author: Ekin Ucuncu, Karthyayani Rajamani, Miranda S. C. Wilson, Daniel Medina-Cano, Nami Altin, Pierre David, Giulia Barcia, Nathalie Lefort, Céline Banal, Marie-Thérèse Vasilache-Dangles, Gaële Pitelet, Elsa Lorino, Nathalie Rabasse, Eric Bieth, Maha S. Zaki, Meral Topcu, Fatma Mujgan Sonmez, Damir Musaev, Valentina Stanley, Christine Bole-Feysot, Patrick Nitschké, Arnold Munnich, Nadia Bahi-Buisson, Catherine Fossoud, Fabienne Giuliano, Laurence Colleaux, Lydie Burglen, Joseph G. Gleeson, Nathalie Boddaert, Adolfo Saiardi, and Vincent Cantagrel
Subjects: Science
Abstract: Tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, the authors describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the MINPP1 gene, characterised by intracellular imbalance of inositol polyphosphate metabolism.
Published: 2020
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7. Impaired telomere integrity and rRNA biogenesis in PARN‐deficient patients and knock‐out models

Author: Maname Benyelles, Harikleia Episkopou, Marie‐Françoise O'Donohue, Laëtitia Kermasson, Pierre Frange, Florian Poulain, Fatma Burcu Belen, Meltem Polat, Christine Bole‐Feysot, Francina Langa‐Vives, Pierre‐Emmanuel Gleizes, Jean‐Pierre de Villartay, Isabelle Callebaut, Anabelle Decottignies, and Patrick Revy
Subjects: Høyeraal–Hreidarsson syndrome, p53, PARN, rRNA, shelterin, Medicine (General), R5-920, Genetics, QH426-470
Abstract: Abstract PARN, poly(A)‐specific ribonuclease, regulates the turnover of mRNAs and the maturation and stabilization of the hTR RNA component of telomerase. Biallelic PARN mutations were associated with Høyeraal–Hreidarsson (HH) syndrome, a rare telomere biology disorder that, because of its severity, is likely not exclusively due to hTR down‐regulation. Whether PARN deficiency was affecting the expression of telomere‐related genes was still unclear. Using cells from two unrelated HH individuals carrying novel PARN mutations and a human PARN knock‐out (KO) cell line with inducible PARN complementation, we found that PARN deficiency affects both telomere length and stability and down‐regulates the expression of TRF1, TRF2, TPP1, RAP1, and POT1 shelterin transcripts. Down‐regulation of dyskerin‐encoding DKC1 mRNA was also observed and found to result from p53 activation in PARN‐deficient cells. We further showed that PARN deficiency compromises ribosomal RNA biogenesis in patients' fibroblasts and cells from heterozygous Parn KO mice. Homozygous Parn KO however resulted in early embryonic lethality that was not overcome by p53 KO. Our results refine our knowledge on the pleiotropic cellular consequences of PARN deficiency.
Published: 2019
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8. High Diagnostic Yield of Targeted Next-Generation Sequencing in a Cohort of Patients With Congenital Hypothyroidism Due to Dyshormonogenesis

Author: Athanasia Stoupa, Ghada Al Hage Chehade, Rim Chaabane, Dulanjalee Kariyawasam, Gabor Szinnai, Sylvain Hanein, Christine Bole-Feysot, Cécile Fourrage, Patrick Nitschke, Caroline Thalassinos, Graziella Pinto, Mouna Mnif, Sabine Baron, Marc De Kerdanet, Rachel Reynaud, Pascal Barat, Mongia Hachicha, Neila Belguith, Michel Polak, and Aurore Carré
Subjects: congenital hypothyroidism, dyshormonogenesis, mutations, targeted next-generation sequencing, gland in situ, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: ObjectiveTo elucidate the molecular cause in a well-characterized cohort of patients with Congenital Hypothyroidism (CH) and Dyshormonogenesis (DH) by using targeted next-generation sequencing (TNGS).Study designWe studied 19 well-characterized patients diagnosed with CH and DH by targeted NGS including genes involved in thyroid hormone production. The pathogenicity of novel mutations was assessed based on in silico prediction tool results, functional studies when possible, variant location in important protein domains, and a review of the recent literature.ResultsTNGS with variant prioritization and detailed assessment identified likely disease-causing mutations in 10 patients (53%). Monogenic defects most often involved TG, followed by DUOXA2, DUOX2, and NIS and were usually homozygous or compound heterozygous. Our review shows the importance of the detailed phenotypic description of patients and accurate analysis of variants to provide a molecular diagnosis.ConclusionsIn a clinically well-characterized cohort, TNGS had a diagnostic yield of 53%, in accordance with previous studies using a similar strategy. TG mutations were the most common genetic defect. TNGS identified gene mutations causing DH, thereby providing a rapid and cost-effective genetic diagnosis in patients with CH due to DH.
Published: 2021
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9. TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology

Author: Athanasia Stoupa, Frédéric Adam, Dulanjalee Kariyawasam, Catherine Strassel, Sanjay Gawade, Gabor Szinnai, Alexandre Kauskot, Dominique Lasne, Carsten Janke, Kathiresan Natarajan, Alain Schmitt, Christine Bole‐Feysot, Patrick Nitschke, Juliane Léger, Fabienne Jabot‐Hanin, Frédéric Tores, Anita Michel, Arnold Munnich, Claude Besmond, Raphaël Scharfmann, François Lanza, Delphine Borgel, Michel Polak, and Aurore Carré
Subjects: congenital hypothyroidism, macroplatelets, mutations, thyroid dysgenesis, TUBB1, Medicine (General), R5-920, Genetics, QH426-470
Abstract: Abstract The genetic causes of congenital hypothyroidism due to thyroid dysgenesis (TD) remain largely unknown. We identified three novel TUBB1 gene mutations that co‐segregated with TD in three distinct families leading to 1.1% of TUBB1 mutations in TD study cohort. TUBB1 (Tubulin, Beta 1 Class VI) encodes for a member of the β‐tubulin protein family. TUBB1 gene is expressed in the developing and adult thyroid in humans and mice. All three TUBB1 mutations lead to non‐functional α/β‐tubulin dimers that cannot be incorporated into microtubules. In mice, Tubb1 knock‐out disrupted microtubule integrity by preventing β1‐tubulin incorporation and impaired thyroid migration and thyroid hormone secretion. In addition, TUBB1 mutations caused the formation of macroplatelets and hyperaggregation of human platelets after stimulation by low doses of agonists. Our data highlight unexpected roles for β1‐tubulin in thyroid development and in platelet physiology. Finally, these findings expand the spectrum of the rare paediatric diseases related to mutations in tubulin‐coding genes and provide new insights into the genetic background and mechanisms involved in congenital hypothyroidism and thyroid dysgenesis.
Published: 2018
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10. Role of miR-146a in neural stem cell differentiation and neural lineage determination: relevance for neurodevelopmental disorders

Author: Lam Son Nguyen, Julien Fregeac, Christine Bole-Feysot, Nicolas Cagnard, Anand Iyer, Jasper Anink, Eleonora Aronica, Olivier Alibeu, Patrick Nitschke, and Laurence Colleaux
Subjects: Autism spectrum disorders, microRNA, Human neural stem cell, Transcriptome, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Background MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression at the post-transcriptional level. miRNAs have emerged as important modulators of brain development and neuronal function and are implicated in several neurological diseases. Previous studies found miR-146a upregulation is the most common miRNA deregulation event in neurodevelopmental disorders such as autism spectrum disorder (ASD), epilepsy, and intellectual disability (ID). Yet, how miR-146a upregulation affects the developing fetal brain remains unclear. Methods We analyzed the expression of miR-146a in the temporal lobe of ASD children using Taqman assay. To assess the role of miR-146a in early brain development, we generated and characterized stably induced H9 human neural stem cell (H9 hNSC) overexpressing miR-146a using various cell and molecular biology techniques. Results We first showed that miR-146a upregulation occurs early during childhood in the ASD brain. In H9 hNSC, miR-146a overexpression enhances neurite outgrowth and branching and favors differentiation into neuronal like cells. Expression analyses revealed that 10% of the transcriptome was deregulated and organized into two modules critical for cell cycle control and neuronal differentiation. Twenty known or predicted targets of miR-146a were significantly deregulated in the modules, acting as potential drivers. The two modules also display distinct transcription profiles during human brain development, affecting regions relevant for ASD including the neocortex, amygdala, and hippocampus. Cell type analyses indicate markers for pyramidal, and interneurons are highly enriched in the deregulated gene list. Up to 40% of known markers of newly defined neuronal lineages were deregulated, suggesting that miR-146a could participate also in the acquisition of neuronal identities. Conclusion Our results demonstrate the dynamic roles of miR-146a in early neuronal development and provide new insight into the molecular events that link miR-146a overexpression to impaired neurodevelopment. This, in turn, may yield new therapeutic targets and strategies.
Published: 2018
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11. AMPA-receptor specific biogenesis complexes control synaptic transmission and intellectual ability

Author: Aline Brechet, Rebecca Buchert, Jochen Schwenk, Sami Boudkkazi, Gerd Zolles, Karine Siquier-Pernet, Irene Schaber, Wolfgang Bildl, Abdelkrim Saadi, Christine Bole-Feysot, Patrick Nitschke, Andre Reis, Heinrich Sticht, Nouriya Al-Sanna’a, Arndt Rolfs, Akos Kulik, Uwe Schulte, Laurence Colleaux, Rami Abou Jamra, and Bernd Fakler
Subjects: Science
Abstract: The biogenesis of AMPA-type glutamate receptor (AMPAR) complexes is only partially understood. Here the authors identify transient assemblies of GluA1-4 proteins and proteins FRRS1l/CPT1c that drive formation of mature AMPAR complexes in the ER. Mutations in FRRS1l are associated with intellectual disability and epilepsy in three families.
Published: 2017
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12. Correction: A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies.

Author: Sara Gonçalves, Julie Patat, Maria Clara Guida, Noelle Lachaussée, Christelle Arrondel, Martin Helmstädter, Olivia Boyer, Olivier Gribouval, Marie-Claire Gubler, Geraldine Mollet, Marlène Rio, Marina Charbit, Christine Bole-Feysot, Patrick Nitschke, Tobias B Huber, Patricia G Wheeler, Devon Haynes, Jane Juusola, Thierry Billette de Villemeur, Caroline Nava, Alexandra Afenjar, Boris Keren, Rolf Bodmer, Corinne Antignac, and Matias Simons
Subjects: Genetics, QH426-470
Abstract: [This corrects the article DOI: 10.1371/journal.pgen.1007386.].
Published: 2018
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13. A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies.

Author: Sara Gonçalves, Julie Patat, Maria Clara Guida, Noelle Lachaussée, Christelle Arrondel, Martin Helmstädter, Olivia Boyer, Olivier Gribouval, Marie-Claire Gubler, Geraldine Mollet, Marlène Rio, Marina Charbit, Christine Bole-Feysot, Patrick Nitschke, Tobias B Huber, Patricia G Wheeler, Devon Haynes, Jane Juusola, Thierry Billette de Villemeur, Caroline Nava, Alexandra Afenjar, Boris Keren, Rolf Bodmer, Corinne Antignac, and Matias Simons
Subjects: Genetics, QH426-470
Abstract: Recent evidence suggests that the presence of more than one pathogenic mutation in a single patient is more common than previously anticipated. One of the challenges hereby is to dissect the contribution of each gene mutation, for which animal models such as Drosophila can provide a valuable aid. Here, we identified three families with mutations in ADD3, encoding for adducin-γ, with intellectual disability, microcephaly, cataracts and skeletal defects. In one of the families with additional cardiomyopathy and steroid-resistant nephrotic syndrome (SRNS), we found a homozygous variant in KAT2B, encoding the lysine acetyltransferase 2B, with impact on KAT2B protein levels in patient fibroblasts, suggesting that this second mutation might contribute to the increased disease spectrum. In order to define the contribution of ADD3 and KAT2B mutations for the patient phenotype, we performed functional experiments in the Drosophila model. We found that both mutations were unable to fully rescue the viability of the respective null mutants of the Drosophila homologs, hts and Gcn5, suggesting that they are indeed pathogenic in flies. While the KAT2B/Gcn5 mutation additionally showed a significantly reduced ability to rescue morphological and functional defects of cardiomyocytes and nephrocytes (podocyte-like cells), this was not the case for the ADD3 mutant rescue. Yet, the simultaneous knockdown of KAT2B and ADD3 synergistically impaired kidney and heart function in flies as well as the adhesion and migration capacity of cultured human podocytes, indicating that mutations in both genes may be required for the full clinical manifestation. Altogether, our studies describe the expansion of the phenotypic spectrum in ADD3 deficiency associated with a homozygous likely pathogenic KAT2B variant and thereby identify KAT2B as a susceptibility gene for kidney and heart disease in ADD3-associated disorders.
Published: 2018
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14. Microdeletion on chromosome 8p23.1 in a familial form of severe Buruli ulcer.

Author: Quentin B Vincent, Aziz Belkadi, Cindy Fayard, Estelle Marion, Ambroise Adeye, Marie-Françoise Ardant, Christian R Johnson, Didier Agossadou, Lazaro Lorenzo, Julien Guergnon, Christine Bole-Feysot, Jeremy Manry, Patrick Nitschké, Ioannis Theodorou, Jean-Laurent Casanova, Laurent Marsollier, Annick Chauty, Laurent Abel, Alexandre Alcaïs, and Franco-Beninese Buruli Research Group
Subjects: Arctic medicine. Tropical medicine, RC955-962, Public aspects of medicine, RA1-1270
Abstract: Buruli ulcer (BU), the third most frequent mycobacteriosis worldwide, is a neglected tropical disease caused by Mycobacterium ulcerans. We report the clinical description and extensive genetic analysis of a consanguineous family from Benin comprising two cases of unusually severe non-ulcerative BU. The index case was the most severe of over 2,000 BU cases treated at the Centre de Dépistage et de Traitement de la Lèpre et de l'Ulcère de Buruli, Pobe, Benin, since its opening in 2003. The infection spread to all limbs with PCR-confirmed skin, bone and joint infections. Genome-wide linkage analysis of seven family members was performed and whole-exome sequencing of both patients was obtained. A 37 kilobases homozygous deletion confirmed by targeted resequencing and located within a linkage region on chromosome 8 was identified in both patients but was absent from unaffected siblings. We further assessed the presence of this deletion on genotyping data from 803 independent local individuals (402 BU cases and 401 BU-free controls). Two BU cases were predicted to be homozygous carriers while none was identified in the control group. The deleted region is located close to a cluster of beta-defensin coding genes and contains a long non-coding (linc) RNA gene previously shown to display highest expression values in the skin. This first report of a microdeletion co-segregating with severe BU in a large family supports the view of a key role of human genetics in the natural history of the disease.
Published: 2018
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15. Comprehensive Identification of Meningococcal Genes and Small Noncoding RNAs Required for Host Cell Colonization

Author: Elena Capel, Aldert L. Zomer, Thomas Nussbaumer, Christine Bole, Brigitte Izac, Eric Frapy, Julie Meyer, Haniaa Bouzinba-Ségard, Emmanuelle Bille, Anne Jamet, Anne Cavau, Franck Letourneur, Sandrine Bourdoulous, Thomas Rattei, Xavier Nassif, and Mathieu Coureuil
Subjects: Microbiology, QR1-502
Abstract: ABSTRACT Neisseria meningitidis is a leading cause of bacterial meningitis and septicemia, affecting infants and adults worldwide. N. meningitidis is also a common inhabitant of the human nasopharynx and, as such, is highly adapted to its niche. During bacteremia, N. meningitidis gains access to the blood compartment, where it adheres to endothelial cells of blood vessels and causes dramatic vascular damage. Colonization of the nasopharyngeal niche and communication with the different human cell types is a major issue of the N. meningitidis life cycle that is poorly understood. Here, highly saturated random transposon insertion libraries of N. meningitidis were engineered, and the fitness of mutations during routine growth and that of colonization of endothelial and epithelial cells in a flow device were assessed in a transposon insertion site sequencing (Tn-seq) analysis. This allowed the identification of genes essential for bacterial growth and genes specifically required for host cell colonization. In addition, after having identified the small noncoding RNAs (sRNAs) located in intergenic regions, the phenotypes associated with mutations in those sRNAs were defined. A total of 383 genes and 8 intergenic regions containing sRNA candidates were identified to be essential for growth, while 288 genes and 33 intergenic regions containing sRNA candidates were found to be specifically required for host cell colonization. IMPORTANCE Meningococcal meningitis is a common cause of meningitis in infants and adults. Neisseria meningitidis (meningococcus) is also a commensal bacterium of the nasopharynx and is carried by 3 to 30% of healthy humans. Under some unknown circumstances, N. meningitidis is able to invade the bloodstream and cause either meningitis or a fatal septicemia known as purpura fulminans. The onset of symptoms is sudden, and death can follow within hours. Although many meningococcal virulence factors have been identified, the mechanisms that allow the bacterium to switch from the commensal to pathogen state remain unknown. Therefore, we used a Tn-seq strategy coupled to high-throughput DNA sequencing technologies to find genes for proteins used by N. meningitidis to specifically colonize epithelial cells and primary brain endothelial cells. We identified 383 genes and 8 intergenic regions containing sRNAs essential for growth and 288 genes and 33 intergenic regions containing sRNAs required specifically for host cell colonization.
Published: 2016
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16. Resequencing microarray technology for genotyping human papillomavirus in cervical smears.

Author: Nicolas Berthet, Michael Falguières, Claudia Filippone, Chloé Bertolus, Christine Bole-Feysot, Sylvain Brisse, Antoine Gessain, Isabelle Heard, and Michel Favre
Subjects: Medicine, Science
Abstract: There are more than 40 human papillomaviruses (HPVs) belonging to the alpha genus that cause sexually transmitted infections; these infections are among the most frequent and can lead to condylomas and anogenital intra-epithelial neoplasia. At least 18 of these viruses are causative agents of anogenital carcinomas. We evaluated the performance of a resequencing microarray for the detection and genotyping of alpha HPV of clinical significance using cloned HPV DNA. To reduce the number of HPV genotypes tiled on microarray, we used reconstructed ancestral sequences (RASs) as they are more closely related to the various genotypes than the current genotypes are among themselves. The performance of this approach was tested by genotyping with a set of 40 cervical smears already genotyped using the commercial PapilloCheck kit. The results of the two tests were concordant for 70% (28/40) of the samples and compatible for 30% (12/40). Our findings indicate that RASs were able to detect and identify one or several HPV in clinical samples. Associating RASs with homonym sequences improved the genotyping of HPV present in cases of multiple infection. In conclusion, we demonstrate the diagnostic potential of resequencing technology for genotyping of HPV, and illustrate its value both for epidemiological studies and for monitoring the distribution of HPV in the post-vaccination era.
Published: 2014
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17. Abnormal Wnt and PI3Kinase signaling in the malformed intestine of lama5 deficient mice.

Author: Léa Ritié, Caroline Spenlé, Joël Lacroute, Anne-Laure Bolcato-Bellemin, Olivier Lefebvre, Christine Bole-Feysot, Bernard Jost, Annick Klein, Christiane Arnold, Michèle Kedinger, Dominique Bagnard, Gertraud Orend, and Patricia Simon-Assmann
Subjects: Medicine, Science
Abstract: Laminins are major constituents of basement membranes and are essential for tissue homeostasis. Laminin-511 is highly expressed in the intestine and its absence causes severe malformation of the intestine and embryonic lethality. To understand the mechanistic role of laminin-511 in tissue homeostasis, we used RNA profiling of embryonic intestinal tissue of lama5 knockout mice and identified a lama5 specific gene expression signature. By combining cell culture experiments with mediated knockdown approaches, we provide a mechanistic link between laminin α5 gene deficiency and the physiological phenotype. We show that laminin α5 plays a crucial role in both epithelial and mesenchymal cell behavior by inhibiting Wnt and activating PI3K signaling. We conclude that conflicting signals are elicited in the absence of lama5, which alter cell adhesion, migration as well as epithelial and muscle differentiation. Conversely, adhesion to laminin-511 may serve as a potent regulator of known interconnected PI3K/Akt and Wnt signaling pathways. Thus deregulated adhesion to laminin-511 may be instrumental in diseases such as human pathologies of the gut where laminin-511 is abnormally expressed as it is shown here.
Published: 2012
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18. Increased immune complexes of hypocretin autoantibodies in narcolepsy.

Author: Aude Deloumeau, Sophie Bayard, Quentin Coquerel, Pierre Déchelotte, Christine Bole-Feysot, Bertrand Carlander, Valérie Cochen De Cock, Sergueï O Fetissov, and Yves Dauvilliers
Subjects: Medicine, Science
Abstract: BACKGROUND: Hypocretin peptides participate in the regulation of sleep-wake cycle while deficiency in hypocretin signaling and loss of hypocretin neurons are causative for narcolepsy-cataplexy. However, the mechanism responsible for alteration of the hypocretin system in narcolepsy-cataplexy and its relevance to other central hypersomnias remain unknown. Here we studied whether central hypersomnias can be associated with autoantibodies reacting with hypocretin-1 peptide present as immune complexes. METHODOLOGY: Serum levels of free and dissociated (total) autoantibodies reacting with hypocretin-1 peptide were measured by enzyme-linked immunosorbent assay and analyzed with regard to clinical parameters in 82 subjects with narcolepsy-cataplexy, narcolepsy without cataplexy or idiopathic hypersomnia and were compared to 25 healthy controls. PRINCIPAL FINDINGS: Serum levels of total but not free IgG autoantibodies against hypocretin-1 were increased in narcolepsy-cataplexy. Increased levels of complexed IgG autoantibodies against hypocretin-1 were found in all patients groups with a further increase in narcolepsy-cataplexy. Levels of total IgM hypocretin-1 autoantibodies were also elevated in all groups of patients. Increased levels of anti-idiotypic IgM autoantibodies reacting with hypocretin-1 IgG autoantibodies affinity purified from sera of subjects with narcolepsy-cataplexy were found in all three groups of patients. Disease duration correlated negatively with serum levels of hypocretin-1 IgG and IgM autoantibodies and with anti-idiotypic IgM autoantibodies. CONCLUSION: Central hypersomnias and particularly narcolepsy-cataplexy are characterized by higher serum levels of autoantibodies directed against hypocretin-1 which are present as immune complexes most likely with anti-idiotypic autoantibodies suggesting their relevance to the mechanism of sleep-wake cycle regulation.
Published: 2010
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19. Sex-dependent effects of a high fat diet on metabolic disorders, intestinal barrier function and gut microbiota in mouse

Author: Candice Lefebvre, Adam Tiffay, Charles-Edward Breemeersch, Virginie Dreux, Christine Bôle-Feysot, Charlène Guérin, Jonathan Breton, Elise Maximin, Magali Monnoye, Pierre Déchelotte, Véronique Douard, Alexis Goichon, and Moïse Coëffier
Subjects: Medicine, Science
Abstract: Abstract Obesity is often associated with sex-dependent metabolic complications, in which altered intestinal barrier function and gut microbiota contribute. We aimed to characterize in mice the sex-dependent effects of a high fat diet on these parameters. Male and female C57BL/6 mice received a standard (SD) or high fat diet (HFD; 60% kcal from fat) during 14 weeks (W14). Body composition, glucose tolerance, insulin sensitivity, intestinal permeability, colonic expression of 44 genes encoding factors involved in inflammatory response and gut barrier function, cecal microbiota, plasma adipokines and white adipose tissue response have been assessed. Both male and female HFD mice exhibited an increase of body weight and fat mass gain and glucose intolerance compared to SD mice. However, only male HFD mice tended to develop insulin resistance associated to increased Tnfα and Ccl2 mRNA expression in perigonadal adipose tissue. By contrast, only female HFD mice showed significant intestinal hyperpermeability that was associated with more markedly altered colonic inflammatory response. Cecal microbiota richness was markedly reduced in both sexes (Observed species) with sex-dependent modifications at the phyla or family level, e.g. decreased relative abundance of Bacillota and Lachnospiraceae in females, increased of Bacteroidaceae in males. Interestingly, some of these microbiota alterations were correlated with peripheral metabolic and inflammatory markers. In conclusions, male and female mice exhibit different responses to a high fat diet with specific changes of gut microbiota, intestinal barrier function, colonic and white adipose tissue inflammation, metabolic markers and body weight gain. The underlying mechanisms should be deciphered in further investigations.
Published: 2024
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20. Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7

Author: Robert A. Hegele, Maria Iascone, Kevin A. Shapiro, Nicolas Chatron, Marwan Shinawi, Joel Charrow, Jeffrey W. Innis, Luitgard Graul-Neumann, Joanna Goes Castro Meira, Anna Lehman, Dawn L. Earl, Victoria R. Sanders, Shannon Rego, David A. Sweetser, Clémantine Dimartino, Wilhelmina S. Kerstjens-Frederikse, Antonio Vitobello, Davor Lessel, Daniel Grinberg, Laurence Faivre, Ryan Peretz, Katherine M. Christensen, Emma Reesor, Erin Beaver, Elizabeth Wohler, Margot R.F. Reijnders, Deborah Barbouth, Anna Cereda, Kaja Kristine Selmer, Melissa A. Walker, Barbro Stadheim, Alessandro Serretti, Helen Kingston, Jill Clayton-Smith, Raymond Lewandowski, Bernarda Lozić, Robert Stratton, Amelia Kirby, Anne H. O’Donnell-Luria, Sara Gabbiadini, Susanna Balcells, Myriam Oufadem, Christel Thauvin, Maha Aly, Wendy K. Chung, Susan M. White, Lauren C. Briere, Thomas Smol, Stanislas Lyonnet, Roberto Colombo, Catherine E. Keegan, Marie T. McDonald, Melanie Parisot, Tiong Yang Tan, Brian Wong, Christopher T. Gordon, Magnus Dehli Vigeland, Frances A. High, Emily Bryant, Audrey Labalme, Nara Sobreira, Arnold Munnich, Jeanne Amiel, Dayna Morel Swols, Raquel Rabionet, Laura Castilla-Vallmanya, Jennifer Heeley, Gunnar Houge, Michael J. Gambello, Bernardo Blanco-Sánchez, Lynn Pais, Olena M. Vaske, Roser Urreizti, Alison Wray, Veronique Pingault, Damien Sanlaville, John Christodoulou, John Millichap, Valérie Cormier-Daire, Parul Jayakar, Helen Cox, Frédéric Tran Mau-Them, Belinda Chong, Victoria Mok Siu, Anne Slavotinek, Antonie J. van Essen, Ingvild Aukrust, Lorne A. Clarke, Rachel Gannaway, Anne Dieux-Coeslier, Patrick Nitschké, Tony Yao, Simon Sadedin, Danielle Karlowicz, Christelle Rougeot, Christine Bole-Feysot, Sandra Yang, Megan T. Cho, Gaetan Lesca, Christiane Zweier, Castilla-Vallmanya L., Selmer K.K., Dimartino C., Rabionet R., Blanco-Sanchez B., Yang S., Reijnders M.R.F., van Essen A.J., Oufadem M., Vigeland M.D., Stadheim B., Houge G., Cox H., Kingston H., Clayton-Smith J., Innis J.W., Iascone M., Cereda A., Gabbiadini S., Chung W.K., Sanders V., Charrow J., Bryant E., Millichap J., Vitobello A., Thauvin C., Mau-Them F.T., Faivre L., Lesca G., Labalme A., Rougeot C., Chatron N., Sanlaville D., Christensen K.M., Kirby A., Lewandowski R., Gannaway R., Aly M., Lehman A., Clarke L., Graul-Neumann L., Zweier C., Lessel D., Lozic B., Aukrust I., Peretz R., Stratton R., Smol T., Dieux-Coeslier A., Meira J., Wohler E., Sobreira N., Beaver E.M., Heeley J., Briere L.C., High F.A., Sweetser D.A., Walker M.A., Keegan C.E., Jayakar P., Shinawi M., Kerstjens-Frederikse W.S., Earl D.L., Siu V.M., Reesor E., Yao T., Hegele R.A., Vaske O.M., Rego S., Shapiro K.A., Wong B., Gambello M.J., McDonald M., Karlowicz D., Colombo R., Serretti A., Pais L., O'Donnell-Luria A., Wray A., Sadedin S., Chong B., Tan T.Y., Christodoulou J., White S.M., Slavotinek A., Barbouth D., Morel Swols D., Parisot M., Bole-Feysot C., Nitschke P., Pingault V., Munnich A., Cho M.T., Cormier-Daire V., Balcells S., Lyonnet S., Grinberg D., Amiel J., Urreizti R., Gordon C.T., MUMC+: DA KG Polikliniek (9), and RS: FHML non-thematic output
Subjects: 0301 basic medicine, NF-KAPPA-B, PROTEIN, 030105 genetics & heredity, medicine.disease_cause, Germline, Transcriptome, ACTIVATION, POLYUBIQUITINATION, Missense mutation, Exome, Genetics (clinical), Genetics, Sanger sequencing, Mutation, leads, Necrosi, craniofacial development, Phenotype, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, intellectual disability, patent ductus arteriosu, symbols, Mutation, Missense, Biology, traf7, Article, akt1, target, 03 medical and health sciences, symbols.namesake, Necrosis, patent ductus arteriosus, medicine, Humans, blepharophimosi, Tumors, MUTATIONS, Fibroblasts, medicine.disease, Blepharophimosis, TRAF7, blepharophimosis, GENOMIC ANALYSIS, Germ Cells, 030104 developmental biology, MENINGIOMAS
Abstract: PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts.METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts.RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts.CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.
Published: 2020

21. Bi-allelic Variations of SMO in Humans Cause a Broad Spectrum of Developmental Anomalies Due to Abnormal Hedgehog Signaling

Author: Lynn Pais, Anna Pelet, Wilhelmina S. Kerstjens-Frederikse, Christine Bole-Feysot, Yunia Sribudiani, Stanislas Lyonnet, Natasha Shur, Valérie Cormier-Daire, Louise Galmiche, Cécile Masson, Christopher T. Gordon, Chelsea Kois, Céline Huber, John A. Pugh, Simon Sadedin, Thuy-Linh Le, Nicolas Goudin, Tania Attié-Bitach, Susan M. White, Tiong Yang Tan, Geneviève Baujat, Valérie Serre, Xiaomin Dong, Mohammed Zarhrate, Patrick Nitschke, Jeanne Amiel, John Christodoulou, Frans W. Verheijen, Sophie Thomas, R Hofstra, Salima El Chehadeh, Valerie Mayne, Université Paris Cité (UPC), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Embryology and genetics of human malformation (Equipe Inserm U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Molecular and Physiopathological bases of osteochondrodysplasia - Bases moléculaires et physiopathologiques des ostéochondrodysplasies (Equipe Inserm U1163), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Genetics and Development of the Cerebral Cortex (Equipe Inserm U1163), Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Clinical Genetics
Subjects: 0301 basic medicine, Male, Models, Molecular, Developmental Disabilities, [SDV]Life Sciences [q-bio], HIRSCHSPRUNG DISEASE, INTRAFLAGELLAR TRANSPORT PROTEIN, ACTIVATION, 0302 clinical medicine, Neoplasms, Sonic hedgehog, Child, Genetics (clinical), Nuclear Proteins, PRIMARY CILIUM, Smoothened Receptor, Hedgehog signaling pathway, Cell biology, Pedigree, Child, Preschool, Female, Signal Transduction, Patched, Nerve Tissue Proteins, Biology, Zinc Finger Protein Gli2, Article, 03 medical and health sciences, HYPOTHALAMIC HAMARTOMA, Zinc Finger Protein Gli3, GLI2, Ciliogenesis, NERVOUS-SYSTEM DEVELOPMENT, Genetics, Humans, Hedgehog Proteins, Cilia, Hedgehog, Alleles, Base Sequence, SONIC HEDGEHOG, MUTATIONS, Infant, CILIARY, 030104 developmental biology, biology.protein, Smoothened, 030217 neurology & neurosurgery, GLI
Abstract: The evolutionarily conserved hedgehog (Hh) pathway is essential for organogenesis and plays critical roles in postnatal tissue maintenance and renewal. A unique feature of the vertebrate Hh pathway is that signal transduction requires the primary cilium (PC) where major pathway components are dynamically enriched. These factors include smoothened (SMO) and patched, which constitute the core reception system for sonic hedgehog (SHH) as well as GLI transcription factors, the key mediators of the pathway. Here, we report biallelic loss-of-function variations in SMO in seven individuals from five independent families; these variations cause a wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis). Cells derived from affected individuals showed normal ciliogenesis but severely altered Hh-signal transduction as a result of either altered PC trafficking or abnormal activation of the pathway downstream of SMO. In addition, Hh-independent GLI2 accumulation at the PC tip in cells from the affected individuals suggests a potential function of SMO in regulating basal ciliary trafficking of GLI2 when the pathway is off. Thus, loss of SMO function results in abnormal PC dynamics of key components of the Hh signaling pathway and leads to a large continuum of malformations in humans.
Published: 2020
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22. Somatic genetic rescue of a germline ribosome assembly defect

Author: Vasileios Kargas, Mélanie Parisot, Norberto Escudero-Urquijo, Alexis Bertrand, Christine Bellanné-Chantelot, Jean Donadieu, Mohammed Zarhrate, Patrick Nitschke, Cécile Masson, Laëtitia Kermasson, Beatriz Goyenechea, Sophie Kaltenbach, Alan J. Warren, David Traynor, Stefano Fumagalli, Li Jin, Blandine Beaupain, Bruno Reversade, Ahmed Z. Boukerrou, Peter J. Bond, M. Rossmann, Olivier Alibeu, Jean-Alain Martignoles, Christine Bole-Feysot, Jonathan Moreil, Shengjiang Tan, François Delhommeau, Patrick Revy, Kong Boo Phua, Alexandre Faille, Aurore Pouliet, Christine Hilcenko, Frédéric Tores, Isabelle Radford-Weiss, Ai Ling Koh, Isabelle Callebaut, Jean-Pierre de Villartay, Cambridge Institute for Medical Research (CIMR), University of Cambridge [UK] (CAM), Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), MRC Laboratory of Molecular Biology [Cambridge, UK] (LMB), University of Cambridge [UK] (CAM)-Medical Research Council, Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), KK Women's and Children's Hospital [Singapore], Genome Institute of Singapore (GIS), Bioinformatics Institute [Singapore], Agency for science, technology and research [Singapore] (A*STAR), National University of Singapore (NUS), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Babraham Research Campus [Cambridge, Royaume-Uni], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Sorbonne Paris Cité (USPC), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ACS - Heart failure & arrhythmias, ARD - Amsterdam Reproduction and Development, Escudero-Urquijo, Norberto [0000-0002-8201-5884], Parisot, Mélanie [0000-0003-4312-2035], Reversade, Bruno [0000-0002-4070-7997], Bond, Peter J. [0000-0003-2900-098X], Bellanné-Chantelot, Christine [0000-0001-8415-6771], Warren, Alan J. [0000-0001-9277-4553], Revy, Patrick [0000-0003-0758-8022], Apollo - University of Cambridge Repository, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Hilcenko, Christine [0000-0002-9596-7833], Rossmann, Maxim [0000-0001-8811-3277], Bond, Peter J [0000-0003-2900-098X], Warren, Alan [0000-0001-9277-4553], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), HAL-SU, Gestionnaire, ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Warren, Alan J [0000-0001-9277-4553]
Subjects: Somatic cell, [SDV]Life Sciences [q-bio], General Physics and Astronomy, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Germline, 631/208/737, 692/699/1541, Ribosome assembly, 13/1, 0302 clinical medicine, hemic and lymphatic diseases, 38/22, Dictyostelium, Eukaryotic Initiation Factors, Child, Cells, Cultured, Biological Phenomena, Genetics, 0303 health sciences, Multidisciplinary, 631/208/514/2254, article, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Ribosome Subunits, Large, Eukaryotic, Ribosome, Shwachman-Diamond Syndrome, 3. Good health, [SDV] Life Sciences [q-bio], 64/24, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, Child, Preschool, Drosophila, Haematological diseases, Protein Binding, Adult, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Science, 45/23, Saccharomyces cerevisiae, Biology, Molecular Dynamics Simulation, General Biochemistry, Genetics and Molecular Biology, 82/80, 03 medical and health sciences, Young Adult, Germline mutation, Animals, Humans, Gene, Ribonucleoprotein, U5 Small Nuclear, 030304 developmental biology, Sequence Homology, Amino Acid, Eukaryotic Large Ribosomal Subunit, Point mutation, Infant, Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, SBDS, 96/44, Peptide Elongation Factors, Germ Cells, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Protein Biosynthesis, Mutation, Next-generation sequencing, 631/337/574/1789, Ribosomes
Abstract: Indirect somatic genetic rescue (SGR) of a germline mutation is thought to be rare in inherited Mendelian disorders. Here, we establish that acquired mutations in the EIF6 gene are a frequent mechanism of SGR in Shwachman-Diamond syndrome (SDS), a leukemia predisposition disorder caused by a germline defect in ribosome assembly. Biallelic mutations in the SBDS or EFL1 genes in SDS impair release of the anti-association factor eIF6 from the 60S ribosomal subunit, a key step in the translational activation of ribosomes. Here, we identify diverse mosaic somatic genetic events (point mutations, interstitial deletion, reciprocal chromosomal translocation) in SDS hematopoietic cells that reduce eIF6 expression or disrupt its interaction with the 60S subunit, thereby conferring a selective advantage over non-modified cells. SDS-related somatic EIF6 missense mutations that reduce eIF6 dosage or eIF6 binding to the 60S subunit suppress the defects in ribosome assembly and protein synthesis across multiple SBDS-deficient species including yeast, Dictyostelium and Drosophila. Our data suggest that SGR is a universal phenomenon that may influence the clinical evolution of diverse Mendelian disorders and support eIF6 suppressor mimics as a therapeutic strategy in SDS., Shwachman-Diamond syndrome (SDS) is a leukemia predisposition disorder that is caused by defective release of eIF6 during ribosome assembly. Here the authors show that acquired somatic EIF6 mutations are frequent in the hematopoietic cells from individuals with SDS and provide a selective advantage over non-modified cells.
Published: 2021
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23. Magnetic resonance colonography assessment of acute trinitrobenzene sulfonic acid colitis in pre-pubertal rats

Author: Lionel Nicol, Mathilde Pala, Christine Bole-Feysot, Charlène Guérin, Guillaume Savoye, Alexis Goichon, Rachel Marion-Letellier, E. Salameh, Claire Dupont-Lucas, Moutaz Aziz, C. Savoye-Collet, Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pédiatrie Médicale [Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Endothélium, valvulopathies et insuffisance cardiaque (EnVI), CHU Rouen, Normandie Université (NU), Equipe Quantification en Imagerie Fonctionnelle (QuantIF-LITIS), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, and douville, sabine
Subjects: Male, Interleukin-1beta, Nitric Oxide Synthase Type II, Pathology and Laboratory Medicine, Gastroenterology, Rats, Sprague-Dawley, Mice, Random Allocation, 0302 clinical medicine, Medicine and Health Sciences, Immune Response, 0303 health sciences, Multidisciplinary, biology, Nitric oxide synthase 2, Colitis, Magnetic Resonance Imaging, 3. Good health, Medicine, 030211 gastroenterology & hepatology, medicine.symptom, Anatomy, Research Article, medicine.medical_specialty, Histology, Colon, Science, Immunology, Histopathology, Inflammation, Gastroenterology and Hepatology, 03 medical and health sciences, Signs and Symptoms, Internal medicine, medicine, Weaning, Ulcerative Colitis, Animals, Acute colitis, 030304 developmental biology, business.industry, Tumor Necrosis Factor-alpha, Inflammatory Bowel Disease, Biology and Life Sciences, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Fibrosis, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, digestive system diseases, Rats, Gastrointestinal Tract, Disease Models, Animal, Trinitrobenzenesulfonic Acid, Anatomical Pathology, Cyclooxygenase 2, biology.protein, Cyclooxygenase, Clinical Medicine, business, Digestive System, Transforming growth factor, Developmental Biology
Abstract: Pre-pubertal murine models of acute colitis are lacking. Magnetic resonance colonography (MRC) is a promising minimally invasive tool to assess colitis. We aimed to: 1/ Adapt a model of acute experimental colitis to pre-pubertal rats and determine whether MRC characteristics correlate with histological inflammation. 2/ Test this model by administering a diet supplemented in transforming growth factor β2 to reverse inflammation. Twenty-four rats were randomized at weaning to one of 3 groups: Trinitrobenzene Sulfonic Acid (TNBS) group (n = 8) fed a standard diet, that received an intra-rectal 60 mg/kg dose of TNBS-ethanol; Control group (n = 8) fed standard diet, that received a dose of intra-rectal PBS; TNBS+MODULEN group (n = 8) that received a dose of TNBS and were exclusively fed MODULEN-IBD® after induction of colitis. One week after induction of colitis, rats were assessed by MRC, colon histopathology and inflammation markers (Interleukin 1β, Tumor necrosis factor α, Nitric Oxide Synthase 2 and Cyclooxygenase 2). TNBS induced typical features of acute colitis on histopathology and MRC (increased colon wall thickness, increased colon intensity on T2-weighted images, target sign, ulcers). Treatment with MODULEN-IBD® did not reduce signs of colitis on MRC. Inflammatory marker expression did not differ among study groups.
Published: 2021
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24. A monocyte/dendritic cell molecular signature of SARS-CoV-2-related multisystem inflammatory syndrome in children with severe myocarditis

Author: Cécile Masson, Aurélien Corneau, Florence Moulin, Ghaith Abdessalem, Pedro Gonçalves, Marianne Leruez, James P. Di Santo, Mathie Lorrot, Julie Toubiana, Julien Haroche, Camille Bruneau, Isabelle Melki, Bruno Charbit, Zahra Belhadjer, Loïc de Pontual, Camille de Cevins, Brigitte Bader Meunier, Alain Fischer, Victor Garcia-Paredes, Brieuc P. Perot, Marine Luka, Damien Bonnet, Quentin Riller, Nikaïa Smith, Slimane Allali, Sonia Meynier, Aude Magérus, Christele Gras Leguen, Shen-Ying Zhang, Olivier Schwartz, Jean-Laurent Casanova, Frédéric Rieux-Laucat, Nicolas Cagnard, Francesco Carbone, Tinhinane Fali, Mélanie Parisot, Mickaël M. Ménager, Maxime Beretta, Mohammed Zarhrate, Christine Bole-Feysot, Vithura Pirabarakan, Ludivine Grzelak, Mehdi Oualha, Darragh Duffy, Laura Barnabei, Hugo Mouquet, Maxime Batignes, Alexandre Boullé, Boris Sorin, Marie-Claude Stolzenberg, Inflammatory Responses and Transcriptomic Networks in diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Sanofi Aventis R&D [Chilly-Mazarin], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP), Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Immunité Innée - Innate Immunity, Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Cytométrie Pitié-Salpêtrière (PASS-CYPS), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Rockefeller University [New York], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP Hôpital universitaire Robert-Debré [Paris], Université Paris Cité (UPCité), CHU Trousseau [APHP], Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Jean Verdier [AP-HP], Université Paris 13 (UP13), Collège de France (CdF (institution)), Biodiversité et Epidémiologie des Bactéries pathogènes - Biodiversity and Epidemiology of Bacterial Pathogens, ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), ANR-17-EURE-0013,GENE,Génétique et Epigénétique Nouvelle Ecole(2017), ANR-18-RHUS-0010,ATRACTION,Autoimmunity/inflammation Through Rnaseq Analysis at the single Cell level for Therapeutic Innovation(2018), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Institut Pasteur [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), and Université Paris Cité (UPC)
Subjects: Adult, Vascular Endothelial Growth Factor A, Chemokine, Myocarditis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], MIS-C, Monocytes, chemistry.chemical_compound, Viewpoint, scRNA-seq, medicine, otorhinolaryngologic diseases, Humans, Kawasaki Disease, Child, Connective Tissue Diseases, biology, business.industry, SARS-CoV-2, Monocyte, NF-kappa B, COVID-19, General Medicine, Dendritic Cells, Gene signature, medicine.disease, Pathophysiology, Systemic Inflammatory Response Syndrome, Vascular endothelial growth factor, medicine.anatomical_structure, Cytokine, chemistry, TNF-α and NF-κB signaling, Immunology, biology.protein, Cytokines, Tumor necrosis factor alpha, lack of responses to type I and type II IFN secretion, Clinical and Translational Article, Chemokines, myocarditis, business, PIMS-TS
Abstract: Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children is generally milder than in adults, but a proportion of cases result in hyperinflammatory conditions often including myocarditis. Methods To better understand these cases, we applied a multiparametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. Plasma cytokine and chemokine levels and blood cellular composition were measured, alongside gene expression at the bulk and single-cell levels. Findings The most severe forms of multisystem inflammatory syndrome in children (MIS-C) related to SARS-CoV-2 that resulted in myocarditis were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomics analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of severe myocarditis characterized by sustained nuclear factor κB (NF-κB) activity and tumor necrosis factor alpha (TNF-α) signaling and associated with decreased gene expression of NF-κB inhibitors. We also found a weak response to type I and type II interferons, hyperinflammation, and response to oxidative stress related to increased HIF-1α and Vascular endothelial growth factor (VEGF) signaling. Conclusions These results provide potential for a better understanding of disease pathophysiology. Funding Agence National de la Recherche (Institut Hospitalo-Universitaire Imagine, grant ANR-10-IAHU-01; Recherche Hospitalo-Universitaire, grant ANR-18-RHUS-0010; Laboratoire d’Excellence ‘‘Milieu Intérieur,” grant ANR-10-LABX-69-01; ANR-flash Covid19 “AIROCovid” and “CoVarImm”), Institut National de la Santé et de la Recherche Médicale (INSERM), and the “URGENCE COVID-19” fundraising campaign of Institut Pasteur., Graphical abstract, Context and significance Children with SARS-CoV-2 infection were initially thought to have only mild COVID-19 symptoms. However, several weeks into the first wave of SARS-CoV-2 infections, there was a surge of a postacute pathology called multisystem inflammatory syndrome in children (MIS-C). The authors recruited a cohort of children with suspicion of SARS-CoV-2 infection and uncovered hyperinflammation, hypoxic conditions, exacerbation of TNF-α signaling via NF-κB, and absence of responses to type I and type II IFN secretion in the most severe forms of MIS-C with severe myocarditis. This work led the authors to identify in monocytes and validate in peripheral blood mononuclear cells a molecular signature of 25 genes that allows discrimination of the most severe forms of MIS-C with myocarditis., Multiparametric analysis identifies, in monocytes and dendritic cells, a molecular signature of the most severe forms of multisystem inflammatory syndrome in children caused by SARS-CoV-2 infection. Severe myocarditis is characterized by an excess of TNF-α signaling via NF-κB, hypoxic conditions, and hyperinflammation in the absence of type I and type II interferon responses.
Published: 2021
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25. A monocyte/dendritic cell molecular signature of SARS-CoV2-related multisystem inflammatory syndrome in children (MIS-C) with severe myocarditis

Author: Ludivine Grzelak, Maxime Beretta, Slimane Allali, Aude Magérus, Hugo Mouquet, Maxime Batignes, Isabelle Melki, Olivier Schwartz, Quentin Riller, Mehdi Oualha, Nicolas Cagnard, Christine Bole-Feysot, Camille de Cevins, James P. Di Santo, Christele Gras Leguen, Florence Moulin, Jean-Laurent Casanova, Cécile Masson, Aurélien Corneau, Damien Bonnet, Vithura Pirabarakan, Mickaël M. Ménager, Camille Bruneau, Brieuc P. Perot, Francesco Carbone, Darragh Duffy, Mohammed Zarhrate, Marie-Claude Stolzenberg, Alexandre Boullé, Mélanie Parisot, Boris Sorin, Ghaith Abdessalem, Alain Fischer, Marianne Leruez, Julie Toubiana, Victor Garcia-Paredes, Mathie Lorrot, Loïc de Pontual, Zahra Belhadjer, Bruno Charbit, Tinhinane Fali, Marine Luka, Nikaïa Smith, Brigitte Bader Meunier, Shen-Ying Zhang, Sonia Meynier, Fredéric Rieux Laucat, Julien Haroche, Pedro Gonçalves, Laura Barnabei, Inflammatory Responses and Transcriptomic Networks in diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Sanofi Aventis R&D [Chilly-Mazarin], Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris], Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunité Innée - Innate Immunity, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Cytométrie Pitié-Salpêtrière (PASS-CYPS), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Rockefeller University [New York], Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Immunologie [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP Hôpital universitaire Robert-Debré [Paris], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département des urgences pédiatriques [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Virologie [CHU Necker], Département de Pédiatrie et maladies infectieuses [CHU Necker], Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Pédiatrie [Jean Verdier], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Nord, Collège de France (CdF (institution)), Biodiversité et Epidémiologie des Bactéries pathogènes - Biodiversity and Epidemiology of Bacterial Pathogens, The study was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), by the 'URGENCE COVID-19' fundraising campaign of Institut Pasteur, by the Atip-Avenir, Emergence ville de Paris program and fond de dotation Janssen Horizon and by government grants managed by the Agence National de la Recherche as part of the 'Investment for the Future' program (Institut Hospitalo-Universitaire Imagine, grant ANR-10-IAHU-01, Recherche Hospitalo-Universitaire, grant ANR-18-RHUS-0010, Laboratoire d’Excellence ‘‘Milieu Intérieur', grant ANR-10-LABX-69-01), the Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), the Agence National de la Recherche (ANR-flash Covid19 'AIROCovid' to FRL and 'CoVarImm' to DD and JDS), and by the FAST Foundation (French Friends of Sheba Tel Hashomer Hospital). The LabTech Single Cell@Imagine is supported by the Paris Region and the 'Investissements d’avenir' program through the 2019 ATF funding – Sésame Filières PIA (Grant N°3877871). CdC is the recipient of a CIFRE-PhD (Sanofi). L.B. was a recipient of an Imagine institute PhD international program supported by the Fondation Bettencourt Schueller. L.B. was also supported by the EUR G.E.N.E. (reference #ANR-17-EURE-0013) and is part of the Université de Paris IdEx #ANR-18-IDEX-0001 funded by the French Government through its 'Investments for the Future' program. S.M. was a recipient of an INSERM and Institut Imagine post-doctorat program supported by the Fondation pour la Recherche Médicale (FRM N°SPF20170938825). NS was a recipient of the Pasteur-Roux-Cantarini Fellowship. VGP obtained an Imagine international PhD fellowship program supported by the Fondation Bettencourt Schueller. BPP is the recipient of an ANRS post-doctoral fellowship., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-18-RHUS-0010,ATRACTION,Autoimmunity/inflammation Through Rnaseq Analysis at the single Cell level for Therapeutic Innovation(2018), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-20-COVI-0022,AIROCovid19,Analyse Omics de la réponse immune aigue au cours de l'infection à Covid19: rationnel moléculaire pour un traitement ciblé(2020), ANR-17-EURE-0013,GENE,Génétique et Epigénétique Nouvelle Ecole(2017), ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: 0303 health sciences, Chemokine, Myocarditis, biology, business.industry, Monocyte, Dendritic cell, Gene signature, medicine.disease_cause, medicine.disease, Pathophysiology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, biology.protein, medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, business, Oxidative stress, 030304 developmental biology
Abstract: SARS-CoV-2 infection in children is generally milder than in adults, yet a proportion of cases result in hyperinflammatory conditions often including myocarditis. To better understand these cases, we applied a multi-parametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. The most severe forms of MIS-C (multisystem inflammatory syndrome in children related to SARS-CoV-2), that resulted in myocarditis, were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomic analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of severe myocarditis, characterized by sustained NF-κB activity, TNF-α signaling, associated with decreased gene expression of NF-κB inhibitors. We also found a weak response to type-I and type-II interferons, hyperinflammation and response to oxidative stress related to increased HIF-1α and VEGF signaling. These results provide potential for a better understanding of disease pathophysiology.
Published: 2021

26. Sex-dependent circadian alterations of both central and peripheral clock genes expression and gut–microbiota composition during activity-based anorexia in mice

Author: Colin Salaün, Marine Courvalet, Léna Rousseau, Kévin Cailleux, Jonathan Breton, Christine Bôle-Feysot, Charlène Guérin, Marion Huré, Alexis Goichon, Jean-Claude do Rego, Pierre Déchelotte, David Ribet, Najate Achamrah, and Moïse Coëffier
Subjects: Medicine, Physiology, QP1-981
Abstract: Abstract Rationale Patients with anorexia nervosa (AN) often present sleep disorders and circadian hormonal dysregulation. The role of the microbiota–gut–brain axis in the regulation of feeding behavior has emerged during the last decades but its relationships with the circadian rhythm remains poorly documented. Thus, we aimed to characterize the circadian clock genes expression in peripheral and central tissues in the activity-based anorexia mouse model (ABA), as well as the dynamics of the gut–microbiota composition. Methods From day 1 to day 17, male and female C57Bl/6 mice were submitted or not to the ABA protocol (ABA and control (CT) groups), which combines a progressive limited access to food and a free access to a running wheel. At day 17, fasted CT and ABA mice were euthanized after either resting (EoR) or activity (EoA) phase (n = 10–12 per group). Circadian clock genes expression was assessed by RT-qPCR on peripheral (liver, colon and ileum) and central (hypothalamic suprachiasmatic nucleus or SCN) tissues. Cecal bacterial taxa abundances were evaluated by qPCR. Data were compared by two-way ANOVA followed by post-tests. Results ABA mice exhibited a lower food intake, a body weight loss and an increase of diurnal physical activity that differ according with the sex. Interestingly, in the SCN, only ABA female mice exhibited altered circadian clock genes expression (Bmal1, Per1, Per2, Cry1, Cry2). In the intestinal tract, modification of clock genes expression was also more marked in females compared to males. For instance, in the ileum, female mice showed alteration of Bmal1, Clock, Per1, Per2, Cry1, Cry2 and Rev-erbα mRNA levels, while only Per2 and Cry1 mRNAs were affected by ABA model in males. By contrast, in the liver, clock genes expression was more markedly affected in males compared to females in response to ABA. Finally, circadian variations of gut–bacteria abundances were observed in both male and female mice and sex-dependent alteration were observed in response to the ABA model. Conclusions This study shows that alteration of circadian clock genes expression at both peripheral and central levels occurs in response to the ABA model. In addition, our data underline that circadian variations of the gut–microbiota composition are sex-dependent.
Published: 2024
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27. Improving the diagnostic efficiency of primary immunodeficiencies with targeted next-generation sequencing

Author: Brigitte Bader-Meunier, Thibault Comont, Felipe Suarez, Alain Fischer, Vincent Barlogis, David Boutboul, Claire Fieschi, Guillaume Vogt, Marlène Pasquet, Frédéric Rieux-Laucat, Jérémie Rosain, Marine Gil, Lionel Galicier, Etienne Merlin, Cécile Fourrage, Christine Bole, Nicholas Renaud, Wadih Abou Chahla, Capucine Picard, Sylvain Hanein, Stéphane Blanche, Patrick Nitschké, Despina Moshous, Benedicte Neven, Isabelle André, Virginie Grandin, Alexandre Alcaïs, Sylvain Latour, Jean-Pierre de Villartay, Chantal Lagresle-Peyrou, Jean-Sebastien Diana, Eric Oksenhendler, Marion Malphettes, Samuel Chevalier, Elisabeth Hulier-Ammar, Olivier Hermine, Mathieu Fusaro, Jacinta Bustamante, Nathalie Lambert, Vivien Béziat, Geneviève de Saint Basile, Nizar Mahlaoui, Martin Castelle, Sven Kracker, Alain Lefevre-Utile, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Subjects: 0301 basic medicine, Adult, Male, Adolescent, Primary Immunodeficiency Diseases, health care facilities, manpower, and services, [SDV]Life Sciences [q-bio], Immunology, education, MEDLINE, Immunoglobulins, Bioinformatics, DNA sequencing, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Immunology and Allergy, Medicine, Guanine Nucleotide Exchange Factors, Humans, Child, health care economics and organizations, Aged, Primary (chemistry), business.industry, Infant, Newborn, High-Throughput Nucleotide Sequencing, Infant, Middle Aged, medicine.disease, 3. Good health, I-kappa B Kinase, 030104 developmental biology, Child, Preschool, Cohort, Mutation, Etiology, Primary immunodeficiency, Female, business, 030215 immunology
Abstract: This study aims to validate a targeted next-generation sequencing panel of 300 genes to diagnose a cohort of 129 patients with primary immunodeficiency with no prior molecular etiology.
Published: 2020
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28. Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function

Author: Marie-Josèphe Tête, Matthias Hansen, Florie Lammens, Tobias Schäfer, Albert Bensman, Alexandra Cambier, Tobias B. Huber, Christoph J. Mache, Elisa Kuhn, Christian Brix Folsted Andersen, Corinne Isnard-Bagnis, Tarunveer S. Ahluwalia, Günter Klaus, Mathilda Bedin, Fabienne Jabot-Hanin, Julien Hogan, Laure Villoing-Gaudé, Timo Wagner, Patrick Nitschke, Carole Tournant, Marcus R. Benz, Maik Grohmann, Markus Gödel, Aude Servais, Corinne Antignac, Cécile Vigneau, Ferielle Louillet, Christine Bole-Feysot, Véronique Baudouin, Iseline Bouteau, Lars Pape, Kay Latta, Carsten Bergmann, Yong Li, Vincent Morinière, Saoussen Krid, Olivier Gribouval, Olivia Boyer, Bruno Ranchin, Anna Köttgen, Matias Simons, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropathies héréditaires et rein en développement, Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Néphrologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], School of Software (THSS), Tsinghua University [Beijing], Néphropathies héréditaires et rein en développement (UMR_S 983), CHU Necker - Enfants Malades [AP-HP]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Hôpital Robert Debré Paris, Hôpital Robert Debré, Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Service de néphrologie et pédiatrie générale [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Service de Néphrologie Rhumatologie Dermatologie, HCL Groupement Hospitalier Est-Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Centre de référence Maladies Rénales Rares, CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'urologie, néphrologie et transplantation [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Department of Pediatric Kidney, Hannover Medical School [Hannover] (MHH)-Children's Hospital, Renal Division, University Medical Center Freiburg, Freiburg, Germany, Service de Génétique Médicale [CHU Necker], Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Plateforme de bioinformatique, Université Paris Descartes - Paris 5 (UPD5), IT University of Copenhagen, NNF18OC0052457, Novo Nordisk Fonden, KO 3598/5-1,KIDGEM SFB1140 246781735, Deutsche Forschungsgemeinschaft, ANR-10-IAHU-01,ANR-14-ACHN-0013, Agence Nationale de la Recherche, 01GM1515C, Federal Ministry or Education and Research, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Tsinghua University [Beijing] (THU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-HCL Groupement Hospitalier Est-Centre de référence Maladies Rénales Rares, Service d'Urologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), IT University of Copenhagen (ITU), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), and ANR-14-ACHN-0013,NEPHROFLY,Utilisation de Drosophila melanogaster pour étudier les maladies génétiques du rein(2014)
Subjects: Male, 0301 basic medicine, Nephrology, medicine.medical_specialty, Anemia, Megaloblastic, [SDV]Life Sciences [q-bio], Renal function, Receptors, Cell Surface, Kidney, urologic and male genital diseases, Gastroenterology, Kidney Tubules, Proximal, 03 medical and health sciences, 0302 clinical medicine, Focal segmental glomerulosclerosis, Malabsorption Syndromes, Internal medicine, Chronic kidney disease, medicine, Genetics, Albuminuria, Humans, Alport syndrome, [SDV.GEN]Life Sciences [q-bio]/Genetics, Proteinuria, business.industry, urogenital system, Vitamin B 12 Deficiency, General Medicine, medicine.disease, Cubilin, female genital diseases and pregnancy complications, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Female, Clinical Medicine, medicine.symptom, business, Nephrotic syndrome, Genetic diseases
Abstract: International audience; BACKGROUNDProteinuria is considered an unfavorable clinical condition that accelerates renal and cardiovascular disease. However, it is not clear whether all forms of proteinuria are damaging. Mutations in CUBN cause Imerslund-Gräsbeck syndrome (IGS), which is characterized by intestinal malabsorption of vitamin B12 and in some cases proteinuria. CUBN encodes for cubilin, an intestinal and proximal tubular uptake receptor containing 27 CUB domains for ligand binding.METHODSWe used next-generation sequencing for renal disease genes to genotype cohorts of patients with suspected hereditary renal disease and chronic proteinuria. CUBN variants were analyzed using bioinformatics, structural modeling, and epidemiological methods.RESULTSWe identified 39 patients, in whom biallelic pathogenic variants in the CUBN gene were associated with chronic isolated proteinuria and early childhood onset. Since the proteinuria in these patients had a high proportion of albuminuria, glomerular diseases such as steroid-resistant nephrotic syndrome or Alport syndrome were often the primary clinical diagnosis, motivating renal biopsies and the use of proteinuria-lowering treatments. However, renal function was normal in all cases. By contrast, we did not found any biallelic CUBN variants in proteinuric patients with reduced renal function or focal segmental glomerulosclerosis. Unlike the more N-terminal IGS mutations, 37 of the 41 proteinuria-associated CUBN variants led to modifications or truncations after the vitamin B12-binding domain. Finally, we show that 4 C-terminal CUBN variants are associated with albuminuria and slightly increased GFR in meta-analyses of large population-based cohorts.CONCLUSIONCollectively, our data suggest an important role for the C-terminal half of cubilin in renal albumin reabsorption. Albuminuria due to reduced cubilin function could be an unexpectedly common benign condition in humans that may not require any proteinuria-lowering treatment or renal biopsy.FUNDINGATIP-Avenir program, Fondation Bettencourt-Schueller (Liliane Bettencourt Chair of Developmental Biology), Agence Nationale de la Recherche (ANR) Investissements d'avenir program (ANR-10-IAHU-01) and NEPHROFLY (ANR-14-ACHN-0013, to MS), Steno Collaborative Grant 2018 (NNF18OC0052457, to TSA and MS), Heisenberg Professorship of the German Research Foundation (KO 3598/5-1, to AK), Deutsche Forschungsgemeinschaft (DFG) Collaborative Research Centre (SFB) KIDGEM 1140 (project 246781735, to CB), and Federal Ministry of Education and Research (BMB) (01GM1515C, to CB).
Published: 2020
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29. High-throughput sequencing of a 4.1Mb linkage interval reveals FLVCR2 deletions and mutations in lethal cerebral vasculopathy

Author: Thomas, Sophie, Encha-Razavi, Ferechté, Devisme, Louise, Etchevers, Heather, Bessieres-Grattagliano, Bettina, Goudefroye, Géraldine, Elkhartoufi, Nadia, Pateau, Emilie, Ichkou, Amale, Bonnière, Maryse, Marcorelle, Pascale, Parent, Philippe, Manouvrier, Sylvie, Holder, Muriel, Laquerrière, Annie, Loeuillet, Laurence, Roume, Joelle, Martinovic, Jelena, Mougou-Zerelli, Soumaya, Gonzales, Marie, Meyer, Vincent, Wessner, Marc, Feysot, Christine Bole, Nitschke, Patrick, Leticee, Nadia, Munnich, Arnold, Lyonnet, Stanislas, Wookey, Peter, Gyapay, Gabor, Foliguet, Bernard, Vekemans, Michel, and Attié-Bitach, Tania
Published: 2010
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30. Germline TIM-3 Mutations Characterize Sub-Cutaneous Panniculitis T-Cell Lymphomas with Hemophagocytic Lymphohistiocytic Syndrome

Author: Simon Gravel, Sylvie Fraitag, Janie Charlebois, Jacek Majewski, Catherine Thieblemont, Rachel Conyers, Brigitte Bader-Meunier, Patrick Nitschke, Tenzin Gayden, Nada Jabado, Fernando E. Sepulveda, Paul G Ekert, Andrea Bajic, Mikko Taipale, Geneviève de Saint Basile, Daniel Schramek, Benedicte Neven, Jean-Sebastien Diana, Dong-Anh Khuong-Quang, Alain Fischer, David Michonneau, David Mitchell, Dzana Dervovic, Frank Sicheri, Maxime Battistella, Elvis Terci Valera, Alexandrine Garrigue, Stéphane Blanche, Despina Moshous, Hamid Nikbakht, Christopher McCormack, Rola Dali, Marianne Besnard, Jonathan Pratt, Nancy Hamel, Sharon Abish, Susan Kelso, H. Miles Prince, Christine Bole-Feysot, Van-Hung Nguyen, Frédéric Guerin, Leonie G. Mikael, William D. Foulkes, The University of MelbourneParkville, VIC, Australia., McGill University = Université McGill [Montréal, Canada], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Sao Paulo (Brazil), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Toronto [Canada], Canadian Centre for Computational Genomics, Montreal, Canada, Sinai Health System, Toronto, Canada, Géosciences Environnement Toulouse (GET), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), McGill University and Genome Quebec Innovation Centre, Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), McGill University Health Center [Montreal] (MUHC), Pediatric Hematology Oncology, Montreal Children's Hosp., Montreal, Canada, Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Immunologie et Hématologie, Space Sciences Laboratory [Berkeley] (SSL), University of California [Berkeley], University of California-University of California, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie pathologique [CHU Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], The Royal Children's Hospital, Melbourne, Australia, Urgences pédiatriques, Hôpital Necker Enfants Malades, Université Paris Descartes, Paris, France, parent, Peter MacCallum Cancer Centre [Melbourne, Australie], Department of Medicine, University of Melbourne, Melbourne, Australia, Centre Hospitalier de Polynésie Française, Service d'immuno-hématologie pédiatrique [CHU Necker], Murdoch Children's Research Institute (MCRI), Laboratoire d'anatomie pathologique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Human Genetics [Montréal], Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Department of Human Genetics , Department of Experimental Medicine, Radboud University Medical Center [Nijmegen], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National d'Études Spatiales [Toulouse] (CNES), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and McGill University
Subjects: T cell, Immunology, Biochemistry, Germline, 03 medical and health sciences, 0302 clinical medicine, Immune system, Medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Hemophagocytic lymphohistiocytosis, Innate immune system, biology, business.industry, Cell Biology, Hematology, medicine.disease, Immune checkpoint, 3. Good health, Lymphoma, medicine.anatomical_structure, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, business, 030215 immunology
Abstract: Introduction Sub-cutaneous panniculitis T-cell lymphomas (SPTCL), a rare non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening activation of the immune system which adversely impacts survival. T-cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T- and innate immune cells. In this work we describe the first germline variants associated with SPTCL, which are in the TIM-3 gene. Methods We sequenced 27 SPTCL cases to identify gene variants. We performed TIM-3 functional analysis on immune cells from patients and HEK293 cells engineered to overexpress wild-type or mutant TIM-3. Results We identified homozygous, germline, loss-of-function, missense variants in highly conserved residues of TIM-3, namely p.Y82C and p.I97M in about 60% (16/27) of SPTCL cases. These samples were drawn from cases series across 3 continents. Patients with bi-allelic TIM-3 mutations were younger at diagnosis, and several had life-threatening HLH and severe disease course. TIM-3 mutations show specific geographic distribution. Y82C TIM-3 mutations occur on a founder chromosome in patients with East-Asian and Polynesian ancestry, while I97M TIM-3 is observed in Caucasians. Both variants induce protein misfolding and cytoplasmic retention of TIM-3. Loss of TIM-3 membrane expression in TIM-3 mutants abrogates the PD-1/PDL-1 checkpoint and prevents the termination of a Th1-immune response. In HEK293 cells, mutant TIM-3 was not expressed on the cell surface. Defective TIM-3 expression leads to persistent immune activation with increased production of inflammatory cytokines including TNF-alpha and IL-1beta by innate immune cells. Conclusion Our findings highlight HLH/SPTCL as a new genetic entity where loss of the TIM-3 immune checkpoint is associated with T-cell infiltration of adipose tissue and inflammasome activation. This is the first causative germline defect identified in SPTCL. While our findings indicate that TIM-3-mutant HLH/SPTCL benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint could have serious adverse consequences. Disclosures Prince: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.
Published: 2019
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31. Effects of Macronutrients on the In Vitro Production of ClpB, a Bacterial Mimetic Protein of α-MSH and Its Possible Role in Satiety Signaling

Author: Charlène Guérin, Manon Dominique, Grégory Lambert, Christine Bole-Feysot, Sergueï O. Fetissov, Jonathan Breton, Pierre Déchelotte, Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), TargEDys Rouen, Service de nutrition [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), and TargEDys SA Rouen
Subjects: 0301 basic medicine, Male, medicine.medical_treatment, medicine.disease_cause, E. coli, Satiety Response, Rats, Sprague-Dawley, 0302 clinical medicine, satiety hormones, Intestinal mucosa, ClpB, Bovine serum albumin, Intestinal Mucosa, Cells, Cultured, Heat-Shock Proteins, 2. Zero hunger, Nutrition and Dietetics, biology, Chemistry, Escherichia coli Proteins, Serum Albumin, Bovine, Endopeptidase Clp, 3. Good health, Biochemistry, Host-Pathogen Interactions, lcsh:Nutrition. Foods and food supply, Signal Transduction, macronutrients, lcsh:TX341-641, 030209 endocrinology & metabolism, Fructose, digestive system, Article, Gene Expression Regulation, Enzymologic, 03 medical and health sciences, medicine, Animals, Secretion, Peptide YY, Escherichia coli, Messenger RNA, Protease, Escherichia coli K12, gut microbiota, PYY, Feeding Behavior, Gene Expression Regulation, Bacterial, Gastrointestinal Microbiome, 030104 developmental biology, biology.protein, CLPB, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Food Science, Oleic Acid
Abstract: Gut microbiota can influence the feeding behavior of the host, but the underlying mechanisms are unknown. Recently, caseinolytic protease B (ClpB), a disaggregation chaperon protein of Escherichia coli, was identified as a conformational mimetic of &alpha, melanocyte-stimulating hormone (&alpha, MSH), an anorexigenic neuropeptide. Importantly, ClpB was necessary for E. coli to have an anorexigenic effect in mice, suggesting that it may participate in satiety signaling. To explore this further, we determined the short-term (2 h) effects of three macronutrients: protein (bovine serum albumin), carbohydrate (D-fructose) and fat (oleic acid), on the production of ClpB by E. coli and analyzed whether ClpB can stimulate the secretion of the intestinal satiety hormone, peptide YY (PYY). Isocaloric amounts of all three macronutrients added to a continuous culture of E. coli increased ClpB immunoreactivity. However, to increase the levels of ClpB mRNA and ClpB protein in bacteria and supernatants, supplementation with protein was required. A nanomolar concentration of recombinant E. coli ClpB dose-dependently stimulated PYY secretion from the primary cell cultures of rat intestinal mucosa. Total proteins extracted from E. coli but not from ClpB-deficient E. coli strains also tended to increase PYY secretion. These data support a possible link between E. coli ClpB and protein-induced satiety signaling in the gut.
Published: 2019
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32. EFL1 mutations impair eIF6 release to cause Shwachman-Diamond syndrome

Author: Dana Ranta, Jean Donadieu, Pekka Jaako, Alan J. Warren, Etienne Lengliné, Laetitia Kermasson, Christine Bellanné-Chantelot, Angela Hoslin, Alexandre Faille, Hubert Ducou Le Pointe, Patrick Revy, Abraham Acevedo-Arozena, Christine Bole-Feysot, Caroline Kannengiesser, Blandine Beaupain, Shengjiang Tan, Patrick Nitschke, Odile Fenneteau, Jean-Pierre de Villartay, Stefano Fumagalli, Maryline Poirée, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, CIC - Biotherapie - GHU Ouest APHP (CIC-BT 502), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hematologie et Médecine Interne, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Pédiatrie, Unité d'Oncologie et Hématologie Pédiatrique, Centre Hospitalier Universitaire de Nice (CHU Nice), Service d'Hématologie Biologique [Hôpital Robert Debré, Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Radiologie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National History Museum of London, Acevedo-Arozena, Abraham [0000-0001-6127-7116], Bellanné-Chantelot, Christine [0000-0001-8415-6771], Warren, Alan J [0000-0001-9277-4553], Revy, Patrick [0000-0003-0758-8022], Apollo - University of Cambridge Repository, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Service d'Hémato-oncologie Pédiatrique, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Saint-Antoine [APHP], Service d’oncologie hématologie pédiatrique [CHU Trousseau], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Male, Models, Molecular, Ribosomopathy, Protein Conformation, DNA Mutational Analysis, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine.disease_cause, Biochemistry, Ribosome, Mice, 0302 clinical medicine, Peptide Initiation Factors, Large ribosomal subunit, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, Genetics, 0303 health sciences, Shwachman–Diamond syndrome, Mutation, Translation (biology), [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Shwachman-Diamond Syndrome, 3. Good health, Pedigree, Phenotype, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, EIF6, 030220 oncology & carcinogenesis, Female, Disease Susceptibility, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Immunology, Mice, Transgenic, Biology, 03 medical and health sciences, Structure-Activity Relationship, Red Cells, Iron, and Erythropoiesis, medicine, Animals, Humans, Ribonucleoprotein, U5 Small Nuclear, 030304 developmental biology, Whole Genome Sequencing, Infant, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, medicine.disease, Peptide Elongation Factors, Disease Models, Animal, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Ribosome Subunits, Genome-Wide Association Study
Abstract: Shwachman-Diamond syndrome (SDS) is a recessive disorder typified by bone marrow failure and predisposition to hematological malignancies. SDS is predominantly caused by deficiency of the allosteric regulator Shwachman-Bodian-Diamond syndrome that cooperates with elongation factor-like GTPase 1 (EFL1) to catalyze release of the ribosome antiassociation factor eIF6 and activate translation. Here, we report biallelic mutations in EFL1 in 3 unrelated individuals with clinical features of SDS. Cellular defects in these individuals include impaired ribosomal subunit joining and attenuated global protein translation as a consequence of defective eIF6 eviction. In mice, Efl1 deficiency recapitulates key aspects of the SDS phenotype. By identifying biallelic EFL1 mutations in SDS, we define this leukemia predisposition disorder as a ribosomopathy that is caused by corruption of a fundamental, conserved mechanism, which licenses entry of the large ribosomal subunit into translation.
Published: 2019
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33. Immunoglobulin G Modulation of the Melanocortin 4 Receptor Signaling in Obesity and Eating Disorders

Author: Sergueï O. Fetissov, Moïse Coëffier, Nicolas Lucas, Jonathan Breton, Jaanus Harro, Christine Bole-Feysot, Anu Järv, Romain Legrand, Pierre Déchelotte, Kirsti Akkermann, Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de nutrition [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), University of Tartu, University Clinics of Tartu, and Différenciation et communication neuronale et neuroendocrine (DC2N)
Subjects: Male, 0301 basic medicine, Physiology, Immunoglobulin G, Rats, Sprague-Dawley, 0302 clinical medicine, Cyclic AMP, Internalization, Receptor, media_common, biology, integumentary system, Middle Aged, 3. Good health, Melanocortin 4 receptor, Psychiatry and Mental health, Receptor, Melanocortin, Type 4, Female, Melanocortin, hormones, hormone substitutes, and hormone antagonists, Signal Transduction, Adult, medicine.medical_specialty, endocrine system, Adolescent, media_common.quotation_subject, Molecular neuroscience, Article, lcsh:RC321-571, Feeding and Eating Disorders, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, Immune system, Internal medicine, medicine, Animals, Humans, Obesity, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, business.industry, Appetite, Mice, Inbred C57BL, HEK293 Cells, 030104 developmental biology, Endocrinology, alpha-MSH, Anorectic, biology.protein, business, Psychiatric disorders, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery
Abstract: Melanocortin 4 receptor (MC4R) plays a key role in regulation of appetite activated by its main ligand α-melanocyte-stimulating hormone (α-MSH) in both central and peripheral targets. α-MSH also binds to circulating immunoglobulins (Igs) but the functional significance of such immune complexes (ICs) in MC4R signaling in normal and pathological conditions of altered appetite has remained unknown. To address this question, we analyzed plasma levels, affinity kinetics, and binding epitopes of α-MSH-reactive IgG extracted from plasma samples of female patients with hyperphagic obesity, anorexia nervosa, bulimia nervosa, binge-eating disorder, and healthy controls. Ability of α-MSH/IgG IC to bind and activate human MC4R were studied in vitro and to influence feeding behavior in vivo in rodents. We found that α-MSH-reactive IgG were low in obese but increased in anorectic and bulimic patients and displayed different epitope and kinetics of IC formation. Importantly, while α-MSH/IgG IC from all subjects were binding and activating MC4R, the receptor binding affinity was decreased in obesity. Additionally, α-MSH/IgG IC had lower MC4R-mediated cAMP activation threshold as compared with α-MSH alone in all but not obese subjects. Furthermore, the cellular internalization rate of α-MSH/IgG IC by MC4R-expressing cells was decreased in obese but increased in patients with anorexia nervosa. Moreover, IgG from obese patients prevented central anorexigenic effect of α-MSH. These findings reveal that MC4R is physiologically activated by IC formed by α-MSH/IgG and that different levels and molecular properties of α-MSH-reactive IgG underlie biological activity of such IC relevant to altered appetite in obesity and eating disorders.
Published: 2019
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34. Alterations of proteome, mitochondrial dynamic and autophagy in the hypothalamus during activity-based anorexia

Author: A. Morin, L. Belmonte, S. Nobis, Najate Achamrah, Pierre Déchelotte, Saïda Azhar, Moïse Coëffier, Charlène Guérin, Alexis Goichon, Jean Claude doÂ Rego, Christine Bole-Feysot, Philippe Chan, David Vaudry, Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Service de nutrition [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), TargEDys Rouen, Plate-forme de Protéomique PISSARO, Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Service Commun d'Analyse Comportementale (SCAC), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Différenciation et communication neuronale et neuroendocrine (DC2N)
Subjects: 0301 basic medicine, Anorexia Nervosa, Proteome, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Receptors, Enterotoxin, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Mitochondrion, Mitochondrial Dynamics, Energy homeostasis, Eating, Mice, Protein Isoforms, Dynamin I, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, Regulation of gene expression, Aconitate Hydratase, Multidisciplinary, digestive, oral, and skin physiology, Anorexia, Hypothalamus, Medicine, Female, medicine.symptom, Microtubule-Associated Proteins, Signal Transduction, medicine.medical_specialty, Science, Biology, Article, 03 medical and health sciences, Internal medicine, Physical Conditioning, Animal, Weight Loss, medicine, Autophagy, Animals, Gene Expression Profiling, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Endocrinology, Gene Expression Regulation, Protein Biosynthesis, Homeostasis
Abstract: Restrictive anorexia nervosa is associated with reduced eating and severe body weight loss leading to a cachectic state. Hypothalamus plays a major role in the regulation of food intake and energy homeostasis. In the present study, alterations of hypothalamic proteome and particularly of proteins involved in energy and mitochondrial metabolism have been observed in female activity-based anorexia (ABA) mice that exhibited a reduced food intake and a severe weight loss. In the hypothalamus, mitochondrial dynamic was also modified during ABA with an increase of fission without modification of fusion. In addition, increased dynamin-1, and LC3II/LC3I ratio signed an activation of autophagy while protein synthesis was increased. In conclusion, proteomic analysis revealed an adaptive hypothalamic protein response in ABA female mice with both altered mitochondrial response and activated autophagy.
Published: 2018
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35. Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome

Author: Fernando E. Sepulveda, Geneviève de Saint Basile, Patrick Nitschke, Stéphane Blanche, Maxime Battistella, David Michonneau, Nada Jabado, Shriya Deshmukh, David Mitchell, Christine Bole-Feysot, Janie Charlebois, Bénédicte Neven, Hamid Nikbakht, Mikko Taipale, Paul G Ekert, Christopher McCormack, William D. Foulkes, Leonie G. Mikael, Alexandrine Garrigue, Dzana Dervovic, Nancy Hamel, Andrea Bajic, Simon Gravel, Despina Moshous, Sharon Abish, Frank Sicheri, Rachel Conyers, Van-Hung Nguyen, Frédéric Guerin, Susan Kelso, Sylvie Fraitag, H. Miles Prince, Jean-Sebastien Diana, Rola Dali, Marianne Besnard, Jonathan Pratt, Elvis Terci Valera, Dong-Anh Khuong-Quang, Catherine Thieblemont, Alain Fischer, Tenzin Gayden, Jacek Majewski, Brigitte Bader-Meunier, Daniel Schramek, Department of Human Genetics [Montréal], McGill University = Université McGill [Montréal, Canada], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Children’s Cancer Center, The Royal Children’s Hospital and Murdoch Children’s Research Institute, Parkville, Victoria, Australia, Department of Pediatrics, University of Melbourne, Parkville, Victoria, Australia, Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Molecular Genetics [Toronto], University of Toronto, Cancer Research Program, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada, Canadian Centre for Computational Genomics, Montreal, Canada, Division of Experimental Medicine [Montréal, QC, Canada] (Department of Medicine), McGill University Health Center [Montreal] (MUHC), Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], Géosciences Environnement Toulouse (GET), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), McGill University and Genome Quebec Innovation Centre, Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pediatric Hematology Oncology, Montreal Children's Hosp., Montreal, Canada, Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Immunologie et Hématologie, Space Sciences Laboratory [Berkeley] (SSL), University of California [Berkeley], University of California-University of California, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie pathologique [CHU Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Department of Pathology, Montreal Children’s Hospital, McGill University Health Centre, Montreal, Quebec, Canada, Département d'Immunologie, hématologie et rhumatologie pédiatriques [Hôpital Necker-Enfants malades - APHP], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Dermatology, St. Vincent’s Hospital, Fitzroy, Victoria, Australia, Department of Oncology [Melbourne, Australie], Peter MacCallum Cancer Centre [Melbourne, Australie], Department of Neonatology, Centre Hospitalier de Polynésie Française, Papeete, French Polynesia, Service d'immuno-hématologie pédiatrique [CHU Necker], epartment of Pediatrics, University of Melbourne, Parkville, Victoria, Australia, Laboratoire d'anatomie pathologique [CHU Necker], Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Department of Human Genetics , Department of Experimental Medicine, Radboud University Medical Center [Nijmegen], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National d'Études Spatiales [Toulouse] (CNES), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and McGill University
Subjects: 0301 basic medicine, Adult, Male, Panniculitis, Adolescent, T cell, [SDV]Life Sciences [q-bio], Biology, HAVCR2, Lymphoma, T-Cell, Lymphohistiocytosis, Hemophagocytic, Diagnosis, Differential, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Immune system, Germline mutation, Subcutaneous Panniculitis-Like T-Cell Lymphoma, Exome Sequencing, Genetics, medicine, T-cell lymphoma, Humans, Genetic Predisposition to Disease, Child, Hepatitis A Virus Cellular Receptor 2, Germ-Line Mutation, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, Hemophagocytic lymphohistiocytosis, [SDV.GEN]Life Sciences [q-bio]/Genetics, Innate immune system, Infant, Middle Aged, medicine.disease, 3. Good health, Pedigree, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female
Abstract: Subcutaneous panniculitis-like T cell lymphoma (SPTCL), a non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune activation that adversely affects survival1,2. T cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T and innate immune cells. We identify in ~60% of SPTCL cases germline, loss-of-function, missense variants altering highly conserved residues of TIM-3, c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met), each with specific geographic distribution. The variant encoding p.Tyr82Cys TIM-3 occurs on a potential founder chromosome in patients with East Asian and Polynesian ancestry, while p.Ile97Met TIM-3 occurs in patients with European ancestry. Both variants induce protein misfolding and abrogate TIM-3’s plasma membrane expression, leading to persistent immune activation and increased production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, promoting HLH and SPTCL. Our findings highlight HLH–SPTCL as a new genetic entity and identify mutations causing TIM-3 alterations as a causative genetic defect in SPTCL. While HLH–SPTCL patients with mutant TIM-3 benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint may have adverse consequences.
Published: 2018
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36. Recurrent RTTN mutation leading to severe microcephaly, polymicrogyria and growth restriction

Author: Laurent Salomon, Camille Maillard, Christine Bole, Patrick Nitschké, Madeline Louise Reilly, Nathalie Boddaert, Amandine Bery, Nadia Bahi-Buisson, Mara Cavallin, Institut des Neurosciences Cellulaires et Intégratives (INCI), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, Pathology, medicine.medical_specialty, Microcephaly, Movement disorders, Encephalopathy, Mutation, Missense, Cell Cycle Proteins, Dwarfism, 03 medical and health sciences, Consanguinity, 0302 clinical medicine, Arachnoid cyst, Databases, Genetic, Genetics, Polymicrogyria, medicine, Missense mutation, Humans, Child, Genetics (clinical), Exome sequencing, business.industry, Homozygote, Brain, General Medicine, medicine.disease, Pedigree, Morocco, 030104 developmental biology, Phenotype, Child, Preschool, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, business, Primordial dwarfism, Carrier Proteins, 030217 neurology & neurosurgery
Abstract: Autosomal recessive missense Rotatin (RTTN) mutations are responsible for syndromic forms of malformation of cortical development, ranging from isolated polymicrogyria to microcephaly associated with primordial dwarfism and other major malformations. We identified, by trio based whole exome sequencing, a homozygous missense mutation in the RTTN gene (c.2953A > G; p.(Arg985Gly)) in one Moroccan patient from a consanguineous family. The patient showed early onset primary microcephaly, detected in the fetal period, postnatal growth restriction, encephalopathy with hyperkinetic movement disorders and self-injurious behavior with sleep disturbance. Brain MRI showed an extensive dysgyria associated with nodular heterotopia, large interhemispheric arachnoid cyst and corpus callosum hypoplasia.
Published: 2018
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37. Correction: A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies

Author: Noelle Lachaussée, Géraldine Mollet, Maria Clara Guida, Olivier Gribouval, Olivia Boyer, Corinne Antignac, Thierry Billette de Villemeur, Martin Helmstädter, Caroline Nava, Rolf Bodmer, Alexandra Afenjar, Jane Juusola, Patrick Nitschke, Sara Gonçalves, Boris Keren, Patricia G. Wheeler, Marina Charbit, Tobias B. Huber, Marie-Claire Gubler, Julie Patat, Marlène Rio, Christelle Arrondel, Matias Simons, Christine Bole-Feysot, and Devon Haynes
Subjects: 0301 basic medicine, Adult, Male, Cancer Research, lcsh:QH426-470, Adolescent, Heart Diseases, DNA Mutational Analysis, Corpus callosum, Bioinformatics, Cell Line, 03 medical and health sciences, Text mining, Cataracts, Genetics, medicine, Animals, Drosophila Proteins, Humans, Abnormalities, Multiple, p300-CBP Transcription Factors, Clinical phenotype, Molecular Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Cells, Cultured, Proteinuria, biology, business.industry, Homozygote, Correction, medicine.disease, biology.organism_classification, Pedigree, lcsh:Genetics, 030104 developmental biology, Phenotype, ADD3, Nasal Diseases, Mutation, Kidney Failure, Chronic, Calmodulin-Binding Proteins, Drosophila, Female, medicine.symptom, Drosophila melanogaster, business
Abstract: Recent evidence suggests that the presence of more than one pathogenic mutation in a single patient is more common than previously anticipated. One of the challenges hereby is to dissect the contribution of each gene mutation, for which animal models such as Drosophila can provide a valuable aid. Here, we identified three families with mutations in ADD3, encoding for adducin-γ, with intellectual disability, microcephaly, cataracts and skeletal defects. In one of the families with additional cardiomyopathy and steroid-resistant nephrotic syndrome (SRNS), we found a homozygous variant in KAT2B, encoding the lysine acetyltransferase 2B, with impact on KAT2B protein levels in patient fibroblasts, suggesting that this second mutation might contribute to the increased disease spectrum. In order to define the contribution of ADD3 and KAT2B mutations for the patient phenotype, we performed functional experiments in the Drosophila model. We found that both mutations were unable to fully rescue the viability of the respective null mutants of the Drosophila homologs, hts and Gcn5, suggesting that they are indeed pathogenic in flies. While the KAT2B/Gcn5 mutation additionally showed a significantly reduced ability to rescue morphological and functional defects of cardiomyocytes and nephrocytes (podocyte-like cells), this was not the case for the ADD3 mutant rescue. Yet, the simultaneous knockdown of KAT2B and ADD3 synergistically impaired kidney and heart function in flies as well as the adhesion and migration capacity of cultured human podocytes, indicating that mutations in both genes may be required for the full clinical manifestation. Altogether, our studies describe the expansion of the phenotypic spectrum in ADD3 deficiency associated with a homozygous likely pathogenic KAT2B variant and thereby identify KAT2B as a susceptibility gene for kidney and heart disease in ADD3-associated disorders.
Published: 2018

38. Targeted therapy in patients with PIK3CA-related overgrowth syndrome

Author: Olivia Boccara, Frank Martinez, Jérémy Sadoine, Christine Bole-Feysot, Christophe Legendre, Valérie Cormier-Daire, Jeanne Amiel, Nicolas Grenier, Clément Hoguin, Sato Magassa, Simon C. Johnson, Thomas Blanc, Junna Yamaguchi, Dominique Joly, Christine Broissand, Caroline Michot, Stéphanie Pannier, Estelle Blanc, J P Duong, Arnaud Picard, Lotfi Slimani, Cécile Laroche-Raynaud, Stanislas Lyonnet, Fabiola Terzi, Nathalie Boddaert, Smail Hadj Rabia, Sabine Sarnacki, Sophia Ladraa, Véronique Soupre, Catherine Chaussain, Laureline Berteloot, Bertrand Knebelmann, Quitterie Venot, Guillaume Canaud, Laurent Guibaud, Pierre Merville, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5), Institut de Mathématiques de Marseille (I2M), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Sorbonne Paris Cité (USPC), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de radiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Service de néphrologie pédiatrique [CHU Necker], Service de Néphrologie-transplantation-dialyse [Bordeaux], CHU Bordeaux [Bordeaux], EHGO, Laboratoire de mécanique des fluides (LMF), École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), Service Néphrologie et transplantation rénale Adultes [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Necker], Service de chirurgie plastique et maxillofaciale [CHU Necker], Pathologies, Imagerie et Biothérapies oro-faciales (EA 2496), Université Paris Descartes - Faculté de Chirurgie Dentaire (UPD5 Odontologie), Service de Radiologie [Hôpital Femme Mère Enfant - HCL], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de néphrologie adultes [CHU Necker], Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Class I Phosphatidylinositol 3-Kinases, Vascular Malformations, [SDV]Life Sciences [q-bio], Scoliosis, Disease, Gastroenterology, Article, Mice, 03 medical and health sciences, Internal medicine, medicine, Animals, Humans, Molecular Targeted Therapy, Child, Nevus, Hemihypertrophy, Survival rate, ComputingMilieux_MISCELLANEOUS, Heart Failure, Sirolimus, Multidisciplinary, business.industry, Organ dysfunction, Genetic disorder, Syndrome, medicine.disease, Vascular Neoplasms, Musculoskeletal Abnormalities, 3. Good health, Disease Models, Animal, Thiazoles, Phenotype, 030104 developmental biology, Overgrowth syndrome, Female, Lipoma, medicine.symptom, business, CLOVES syndrome, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, HeLa Cells
Abstract: CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.
Published: 2018
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39. Role of miR-146a in neural stem cell differentiation and neural lineage determination: relevance for neurodevelopmental disorders

Author: Olivier Alibeu, Lam Son Nguyen, Julien Fregeac, Eleonora Aronica, Christine Bole-Feysot, Anand Iyer, Patrick Nitschké, Laurence Colleaux, Jasper J. Anink, Nicolas Cagnard, Pathology, ANS - Cellular & Molecular Mechanisms, APH - Aging & Later Life, APH - Mental Health, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Genome Analysis, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, MESH: Neural Stem Cells, Male, Human neural stem cell, Autism Spectrum Disorder, lcsh:RC346-429, Transcriptome, Neural Stem Cells, MESH: Child, MESH: Up-Regulation, Child, MESH: Autism Spectrum Disorder, Neocortex, microRNA, Human brain, Autism spectrum disorders, Neural stem cell, Temporal Lobe, Up-Regulation, Psychiatry and Mental health, medicine.anatomical_structure, Female, Cell type, Neurite, Neurogenesis, Biology, Cell Line, 03 medical and health sciences, Developmental Neuroscience, Downregulation and upregulation, medicine, MESH: Temporal Lobe, Humans, Cell Lineage, Molecular Biology, lcsh:Neurology. Diseases of the nervous system, MESH: Humans, Research, MESH: Cell Lineage, MESH: Male, MESH: Cell Line, MESH: Neurogenesis, MicroRNAs, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neuroscience, MESH: Female, MESH: MicroRNAs, Developmental Biology
Abstract: Background MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression at the post-transcriptional level. miRNAs have emerged as important modulators of brain development and neuronal function and are implicated in several neurological diseases. Previous studies found miR-146a upregulation is the most common miRNA deregulation event in neurodevelopmental disorders such as autism spectrum disorder (ASD), epilepsy, and intellectual disability (ID). Yet, how miR-146a upregulation affects the developing fetal brain remains unclear. Methods We analyzed the expression of miR-146a in the temporal lobe of ASD children using Taqman assay. To assess the role of miR-146a in early brain development, we generated and characterized stably induced H9 human neural stem cell (H9 hNSC) overexpressing miR-146a using various cell and molecular biology techniques. Results We first showed that miR-146a upregulation occurs early during childhood in the ASD brain. In H9 hNSC, miR-146a overexpression enhances neurite outgrowth and branching and favors differentiation into neuronal like cells. Expression analyses revealed that 10% of the transcriptome was deregulated and organized into two modules critical for cell cycle control and neuronal differentiation. Twenty known or predicted targets of miR-146a were significantly deregulated in the modules, acting as potential drivers. The two modules also display distinct transcription profiles during human brain development, affecting regions relevant for ASD including the neocortex, amygdala, and hippocampus. Cell type analyses indicate markers for pyramidal, and interneurons are highly enriched in the deregulated gene list. Up to 40% of known markers of newly defined neuronal lineages were deregulated, suggesting that miR-146a could participate also in the acquisition of neuronal identities. Conclusion Our results demonstrate the dynamic roles of miR-146a in early neuronal development and provide new insight into the molecular events that link miR-146a overexpression to impaired neurodevelopment. This, in turn, may yield new therapeutic targets and strategies. Electronic supplementary material The online version of this article (10.1186/s13229-018-0219-3) contains supplementary material, which is available to authorized users.
Published: 2018
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40. Novel de novo ZBTB20 mutations in three cases with Primrose syndrome and constant corpus callosum anomalies

Author: Maryse Bonnière, Férechté Encha-Razavi, Yves Ville, Lucile Boutaud, Laurence Colleaux, Charlotte Mechler, Patrick Nitschke, Valérie Cormier-Daire, Bettina Bessières, Judith de Oliveira, Philippe Roth, Linda Mouthon, Tania Attié-Bitach, Christine Bole, Nadia Bahi-Buisson, Nathalie Boddaert, Valérie Serre, Caroline Alby, Stanislas Lyonnet, Marlène Rio, Amale Ichkou, Sophie Thomas, Michel Vekemans, Christopher T. Gordon, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie pédiatrique [CHU Necker], Service de radiologie pédiatrique [CHU Necker], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
Subjects: 0301 basic medicine, Male, Candidate gene, Adolescent, Protein Conformation, Nerve Tissue Proteins, Biology, Corpus callosum, 03 medical and health sciences, 0302 clinical medicine, Brain commissure, Intellectual Disability, Genetics, medicine, Humans, Abnormalities, Multiple, Megalencephaly, Amino Acid Sequence, Child, Ear Diseases, Genetics (clinical), Exome sequencing, Zinc finger, Macrocephaly, Infant, Newborn, Brain, Calcinosis, High-Throughput Nucleotide Sequencing, Reproducibility of Results, Sequence Analysis, DNA, medicine.disease, Primrose syndrome, 3. Good health, Pedigree, Muscular Atrophy, 030104 developmental biology, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Nucleic Acid Conformation, Female, medicine.symptom, Agenesis of Corpus Callosum, 030217 neurology & neurosurgery, Transcription Factors
Abstract: International audience; Corpus callosum (CC) is the major brain commissure connecting homologous areas of cerebral hemispheres. CC anomalies (CCAs) are the most frequent brain anomalies leading to variable neurodevelopmental outcomes making genetic counseling difficult in the absence of a known etiology that might inform the prognosis. Here, we used whole exome sequencing, and a targeted capture panel of syndromic CCA known causal and candidate genes to screen a cohort of 64 fetuses with CCA observed upon autopsy, and 34 children with CCA and intellectual disability. In one fetus and two patients, we identified three novel de novo mutations in ZBTB20, which was previously shown to be causal in Primrose syndrome. In addition to CCA, all cases presented with additional features of Primrose syndrome including facial dysmorphism and macrocephaly or megalencephaly. All three variations occurred within two out of the five zinc finger domains of the transcriptional repressor ZBTB20. Through homology modeling, these variants are predicted to result in local destabilization of each zinc finger domain suggesting subsequent abnormal repression of ZBTB20 target genes. Neurohistopathological analysis of the fetal case showed abnormal regionalization of the hippocampal formation as well as a reduced density of cortical upper layers where originate most callosal projections. Here, we report novel de novo ZBTB20 mutations in three independent cases with characteristic features of Primrose syndrome including constant CCA. Neurohistopathological findings in fetal case corroborate the observed key role of ZBTB20 during hippocampal and neocortical development. Finally, this study highlights the crucial role of ZBTB20 in CC development in human.
Published: 2018
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41. Functional characterization of tektin-1 in motile cilia and evidence for TEKT1 as a new candidate gene for motile ciliopathies

Author: Alexandre Benmerah, Estelle Escudier, Christine Bole-Feysot, Véronique Baudouin, Thérèse Reboul, Patrick Nitschké, Marie Legendre, Marion Delous, Sophie Saunier, Meriem Garfa-Traore, Rebecca Ryan, Madeline Louise Reilly, Marion Failler, Serge Amselem, Emilie Filhol, Laboratoire des Maladies Rénales Héréditaires, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Plateforme d'Imagerie Cellulaire [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Bioinformatics Core Facility (INSERM U1163), Sorbonne Paris Cité-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Néphrologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Benmerah, Alexandre, Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], and UF de Génétique moléculaire [CHU Trousseau]
Subjects: 0301 basic medicine, Axoneme, [SDV]Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, Ciliopathies, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 0302 clinical medicine, Ectodermal Dysplasia, Exome, Child, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Zebrafish, Genetics (clinical), Primary ciliary dyskinesia, Cilium, Intracellular Signaling Peptides and Proteins, General Medicine, Cell biology, [SDV] Life Sciences [q-bio], Phenotype, Microtubule Proteins, Motile cilium, Female, Retinitis Pigmentosa, Ciliary Motility Disorders, Cerebellar Ataxia, Ciliary dyskinesia, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Bone and Bones, Craniosynostoses, 03 medical and health sciences, Exome Sequencing, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Genetics, medicine, Animals, Humans, Cilia, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Tektin, Proteins, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Cytoskeletal Proteins, 030104 developmental biology, Mutation, Cranioectodermal Dysplasia, 030217 neurology & neurosurgery
Abstract: International audience; A child presenting with Mainzer-Saldino syndrome (MZSDS), characterized by renal, retinal and skeletal involvements, was also diagnosed with lung infections and airway ciliary dyskinesia. These manifestations suggested dysfunction of both primary and motile cilia, respectively. Targeted exome sequencing identified biallelic mutations in WDR19, encoding an IFT-A subunit previously associated with MZSDS-related chondrodysplasia, Jeune asphyxiating thoracic dysplasia and cranioectodermal dysplasia, linked to primary cilia dysfunction, and in TEKT1 which encodes tektin-1 an uncharacterized member of the tektin family, mutations of which may cause ciliary dyskinesia. Tektin-1 localizes at the centrosome in cycling cells, at basal bodies of both primary and motile cilia and to the axoneme of motile cilia in airway cells. The identified mutations impaired these localizations. In addition, airway cells from the affected individual showed severe motility defects without major ultrastructural changes. Knockdown of tekt1 in zebrafish resulted in phenotypes consistent with a function for tektin-1 in ciliary motility, which was confirmed by live imaging. Finally, experiments in the zebrafish also revealed a synergistic effect of tekt1 and wdr19. Altogether, our data show genetic interactions between WDR19 and TEKT1 likely contributing to the overall clinical phenotype observed in the affected individual and provide strong evidence for TEKT1 as a new candidate gene for primary ciliary dyskinesia.
Published: 2018
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42. Recessive loss of function PIGN alleles, including an intragenic deletion with founder effect in La Réunion Island, in patients with Fryns syndrome

Author: Asma Chebil, Duksha Ramful, Thibaud Jouan, Hanitra Randrianaivo, Norbert F. Ajeawung, Nicolas Gruchy, Yannis Duffourd, Bérénice Doray, Christopher T. Gordon, Francesca Filippini, Christine Bole-Feysot, Philippe M. Campeau, Asma Omarjee, Julien Thevenon, Paul Kuentz, Jean-Luc Alessandri, Patrick Nitschke, Laurence Faivre, Jeanne Amiel, Coralie Dumont, Thi Tuyet Mai Nguyen, Marion Gérard, Myriam Oufadem, Guillaume Benoist, Olivier Alibeu, Marie-Line Jacquemont, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Sud Saint Pierre [Ile de la Réunion], Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre de recherche du CHU Sainte-Justine, CHU Sainte Justine [Montréal], Centre Hospitalier de Mayotte, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche du CHU Sainte-Justine [Montreal], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Service de réanimation néonatologique et pédiatrique [La Réunion], Groupe Hospitalier Sud-CHR La réunion, Embryology and genetics of human malformation (Equipe Inserm U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Pôle Gynécologie Obstétrique [CHM, Mayotte], Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Pôle Femme-Mère-Enfant [CHU La Réunion, Saint-Pierre, La Réunion], Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biologie moléculaire et cellulaire de la différenciation, Université Joseph Fourier - Grenoble 1 (UJF)-Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de La Réunion ( CHU La Réunion ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Service de Génétique Clinique [Caen], Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -CHU Caen, Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Laboratoire de Génétique Médicale ( LGM ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Réanimation Néonatale et Pédiatrique, CHD Félix Guyon, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Université de Lausanne (UNIL), Laboratoire de Chimie Physique Macromoléculaire (LCPM), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Equipe NuTox (LNC - U1231) (NUTOX), Service de Médecine Néonatale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université de Maurice, Service de médecine foetale et foetopathologie, Service de Génétique, Hôpital de Hautepierre [Strasbourg], Department of Experimental Cardiology, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), and University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Heart Failure Research Center (HFRC)
Subjects: 0301 basic medicine, Male, MESH: Limb Deformities, Congenital, Limb Deformities, Congenital, MESH: Phosphotransferases, [SDV.CAN]Life Sciences [q-bio]/Cancer, 030105 genetics & heredity, Biology, MESH: Founder Effect, Article, 03 medical and health sciences, Pulmonary hypoplasia, 0302 clinical medicine, Fryns syndrome, Loss of Function Mutation, Genetics, medicine, Missense mutation, Humans, Allele, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics (clinical), Loss function, Hernia, Diaphragmatic, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Phosphotransferases, MESH: Infant, Newborn, Infant, Newborn, Congenital diaphragmatic hernia, Facies, Infant, MESH: Loss of Function Mutation, medicine.disease, MESH: Infant, Hypoplasia, Founder Effect, MESH: Male, MESH: Hernia, Diaphragmatic, MESH: Facies, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Gene Deletion, Female, MESH: Female, 030217 neurology & neurosurgery, Gene Deletion, Founder effect
Abstract: International audience; Fryns syndrome (FS) is a multiple malformations syndrome with major features of congenital diaphragmatic hernia, pulmonary hypoplasia, craniofacial dysmorphic features, distal digit hypoplasia, and a range of other lower frequency malformations. FS is typically lethal in the fetal or neonatal period. Inheritance is presumed autosomal recessive. Although no major genetic cause has been identified for FS, biallelic truncating variants in PIGN, encoding a component of the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway, have been identified in a limited number of cases with a phenotype compatible with FS. Biallelic variants in PIGN, typically missense or compound missense with truncating, also cause multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1). Here we report six further patients with FS with or without congenital diaphragmatic hernia and recessive loss of function PIGN alleles, including an intragenic deletion with a likely founder effect in La Réunion and other Indian Ocean islands. Our results support the hypothesis that a spectrum of phenotypic severity is associated with recessive PIGN variants, ranging from FS at the extreme end, caused by complete loss of function, to MCAHS1, in which some residual PIGN function may remain. Our data add FS resulting from PIGN variants to the catalog of inherited GPI deficiencies caused by the disruption of the GPI-anchor biosynthesis pathway.
Published: 2018
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43. MMP21 is mutated in human heterotaxy and is required for normal left-right asymmetry in vertebrates

Author: Cecilia W. Lo, Cécile Masson, Molly Schwartz, Rajae El Malti, Loïc de Pontual, G Jimenez, George C. Gabriel, Nikolai Klena, Hui Liu, Hisato Yagi, Candice N. Baker, Sylvie Di Filippo, Christopher T. Gordon, Damien Bonnet, Michael Tsang, Patric Schoen, Myriam Oufadem, Isabelle Thiffault, Laurie D. Smith, Linda D. Cooley, Anne Moreau de Bellaing, Patrick Nitschké, Patrice Bouvagnet, Emily G. Farrow, Anne Guimier, Aaron Noll, Fanny Bajolle, Carol J Saunders, Stephen F. Kingsmore, Kevin A. Peterson, Neil A. Miller, Jean-François Deleuze, Stanislas Lyonnet, Stephen A. Murray, Jeanne Amiel, and Christine Bole-Feysot
Subjects: Heart Defects, Congenital, Male, medicine.medical_specialty, Embryo, Nonmammalian, Genes, Recessive, In situ hybridization, Heterotaxy Syndrome, Article, Mice, Matrix Metalloproteinases, Secreted, Genetics, medicine, Animals, Humans, Point Mutation, Zebrafish, In Situ Hybridization, Body Patterning, Family Health, biology, MMP21, Point mutation, Embryogenesis, Gene Expression Regulation, Developmental, Heart, Sequence Analysis, DNA, Zebrafish Proteins, biology.organism_classification, Pedigree, Laterality, Vertebrates, Medical genetics, Female, Heterotaxy
Abstract: Heterotaxy results from a failure to establish normal left-right asymmetry early in embryonic development. By whole-exome sequencing, whole-genome sequencing and high-throughput cohort resequencing, we identified recessive mutations in MMP21 (encoding matrix metallopeptidase 21) in nine index cases with heterotaxy. In addition, Mmp21-mutant mice and mmp21-morphant zebrafish displayed heterotaxy and abnormal cardiac looping, respectively, suggesting a new role for extracellular matrix remodeling in the establishment of laterality in vertebrates.
Published: 2015

44. A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations

Author: Susan Brammah, Honey Nagakura, Christopher T. Gordon, Laurence Hubert, Andrea M. Lewis, Renee Carroll, Richard H. Scott, Alexandrine Garrigue, Melanie Leffler, Jozef Gecz, Michael Field, Lucinda Murray, Sarah Risen, Seema R. Lalani, Marie Shaw, Geneviève de Saint Basile, Augusto Rendon, Raman Kumar, Tracy Dudding-Byth, LaDonna Immken, Patrick Nitschké, Arnold Munnich, Jeanne Amiel, Mark J. Cowley, Judy Spies, Bronwyn Kerr, Myriam Oufadem, Nina Powell-Hamilton, Claude Besmond, John D. Pollard, Emma Kivuva, Christine Bole-Feysot, William G. Newman, Jill A. Rosenfeld, Elizabeth E. Palmer, Jessica Tusi, Allison Tam, Richard Webster, Francesca Filippini, Marlène Rio, André E. Minoche, and Fan Xia
Subjects: 0301 basic medicine, Central Nervous System, media_common.quotation_subject, Nonsense, Limb Deformities, Congenital, Neurocognitive Disorders, Bioinformatics, 03 medical and health sciences, Exon, Report, Intellectual Disability, Intellectual disability, Peripheral Nervous System, Genetics, medicine, Journal Article, Missense mutation, Humans, Craniofacial, Gene, Genetics (clinical), media_common, business.industry, High-Throughput Nucleotide Sequencing, medicine.disease, Phenotype, DNA-Binding Proteins, 030104 developmental biology, medicine.anatomical_structure, Codon, Nonsense, Peripheral nervous system, business, Mandibulofacial Dysostosis
Abstract: A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations. We show that the c.2737C>T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect. This study builds support for a key role for ZSWIM6 in neuronal development and function, in addition to its putative roles in limb and craniofacial development, and provides a striking example of different variants in the same gene leading to distinct phenotypes.
Published: 2017
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45. Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice

Author: Bertrand Isidor, Christelle Arrondel, Camille Humbert, Flora Silbermann, Marie-Hélène Said-Menthon, Cécile Jeanpierre, Christelle Cabrol, Audrey Desgrange, Frédéric Tores, Laurence Heidet, Lara De Tomasi, Ishwar C. Verma, Marie-Pierre Cordier, Ratna Dua Puri, Laurent Gavard, Jelena Martinovic, Christine Pietrement, Juliette Piard, Olivier Niel, Marie Gonzales, Patrick Nitschke, Robert Novo, Stéphane Fouquet, Joelle Roume, Philippe Khau Van Kien, Jacqueline Aziza, Pierre David, Sophie Saunier, Marie-Hélène Saint-Frison, Hubert Journel, Christine Bole-Feysot, The molecular basis of kidney diseases: cystinosis and hereditary nephrotic syndrome (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Coordination des Cellules et Morphogenèse / Heart Morphogenesis (Imagine - Institut Pasteur U1163), Institut Pasteur [Paris] (IP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Hôpital Robert Debré Paris, Hôpital Robert Debré, CHI Poissy-Saint-Germain, Centre Hospitalier Universitaire de Reims (CHU Reims), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Lille, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), and Sir Ganga Ram Hospital [New Delhi, India]
Subjects: 0301 basic medicine, Male, nephrogenesis, 030105 genetics & heredity, Kidney, Mice, Missense mutation, Exome, Child, Urinary Tract, Genetics (clinical), Exome sequencing, kidney development, Mice, Knockout, kidney agenesis, heart defect, tubulogenesis, Hypoplasia, Neoplasm Proteins, medicine.anatomical_structure, Phenotype, Agenesis, Female, Kidney Diseases, medicine.medical_specialty, Heterozygote, Urinary system, mouse model, Biology, Congenital Abnormalities, 03 medical and health sciences, Fetus, Internal medicine, Report, Genetics, medicine, Animals, Humans, Renal agenesis, CAKUT, Membrane Proteins, Proteins, genital tract, [SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis, medicine.disease, 3DISCO, GREB1L, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Urogenital Abnormalities, Mutation, Kidney disease
Abstract: International audience; Congenital anomalies of the kidney and urinary tract (CAKUT) constitute a major cause of chronic kidney disease in children and 20% of prenatally detected anomalies. CAKUT encompass a spectrum of developmental kidney defects, including renal agenesis, hypoplasia, and cystic and non-cystic dysplasia. More than 50 genes have been reported as mutated in CAKUT-affected case subjects. However, the pathophysiological mechanisms leading to bilateral kidney agenesis (BKA) remain largely elusive. Whole-exome or targeted exome sequencing of 183 unrelated familial and/or severe CAKUT-affected case subjects, including 54 fetuses with BKA, led to the identification of 16 heterozygous variants in GREB1L (growth regulation by estrogen in breast cancer 1-like), a gene reported as a target of retinoic acid signaling. Four loss-of-function and 12 damaging missense variants, 14 being absent from GnomAD, were identified. Twelve of them were present in familial or simplex BKA-affected case subjects. Female BKA-affected fetuses also displayed uterus agenesis. We demonstrated a significant association between GREB1L variants and BKA. By in situ hybridization, we showed expression of Greb1l in the nephrogenic zone in developing mouse kidney. We generated a Greb1l knock-out mouse model by CRISPR-Cas9. Analysis at E13.5 revealed lack of kidneys and genital tract anomalies in male and female Greb1l-/- embryos and a slight decrease in ureteric bud branching in Greb1l+/- embryos. We showed that Greb1l invalidation in mIMCD3 cells affected tubulomorphogenesis in 3D-collagen culture, a phenotype rescued by expression of the wild-type human protein. This demonstrates that GREB1L plays a major role in early metanephros and genital development in mice and humans.
Published: 2017
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46. A RAB27A duplication in several cases of Griscelli syndrome type 2: An explanation for cases lacking a genetic diagnosis

Author: Fahd Almanjomi, Eman Al Idrissi, Capucine Picard, Nathalie Lambert, Patrick Nitschke, Gaël Ménasché, Mofareh Al Zahrani, Hamza Ali Alghamdi, Virginie Grandin, Fernando E. Sepulveda, Geneviève de Saint Basile, Murad K. Habazi, Hamoud Al-Mousa, Abdulaziz Al-Ghonaium, Christine Bole-Feysot, Centre d’Etudes des Déficits Immunitaires (CHU Necker - Enfants Malades [AP-HP]), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sorbonne Paris Cité (USPC), Allergy and Immunology Section [Riyadh, Saudi Arabia] (Children Specialized Hospital), King Fahad Medical City [Riyadh, Saudi Arabia], Département d'Immunologie, hématologie et rhumatologie pédiatriques [Hôpital Necker-Enfants malades - APHP], Plateforme de Génomique [Paris] (Fondation Imagine), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Plateforme de bioinformatique (UNIV Paris Descartes), Université Paris Descartes - Paris 5 (UPD5), Contract grant sponsors: French National Institute of Health and Medical Research (INSERM), the Agence National de la Recherche (ANR) (HLH-Cytotox/ANR-12-BSV1-0020-01), the Fondation Imagine-Institut des Maladies Génétiques., Ménasché, Gaël, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Subjects: 0301 basic medicine, Male, Genetic Linkage, [SDV]Life Sciences [q-bio], Skin Pigmentation, rab27 GTP-Binding Proteins, Consanguinity, Gene duplication, Pigment accumulation, Griscelli syndrome, Genetics (clinical), Sequence Deletion, Genetics, Hypopigmentation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Homozygote, Piebaldism, Exons, 3. Good health, Pedigree, [SDV] Life Sciences [q-bio], founder effect, Codon, Nonsense, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Tandem exon duplication, Primary Immunodeficiency Diseases, Saudi Arabia, Biology, Lymphohistiocytosis, Hemophagocytic, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Indel, Point mutation, RAB27A, Breakpoint, Immunologic Deficiency Syndromes, gene duplication, medicine.disease, 030104 developmental biology, Griscelli syndrome type 2, Mutation, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Hair, T-Lymphocytes, Cytotoxic
Abstract: International audience; Griscelli syndrome type 2 (GS2) is a rare and often fatal autosomal recessive, hyperinflammatory disorder. It is associated with hypopigmentation of the skin and the hair, resulting in the characteristic pigment accumulation and clumping in the hair shaft. Loss-of-function mutations in RAB27A, resulting from point mutations, short indel, or large deletions, account for all the cases reported to date. However, several GS2 cases originating from Saudi Arabia lack a genetic diagnosis. Here, we report on a new RAB27A genetic anomaly observed in seven Saudi Arabia families that had remained negative after extensive molecular genomic DNA testing. Linkage analysis and targeted sequencing of the RAB27A genomic region in several of these patients led to the identification of a common homozygous tandem duplication of 38 kb affecting exon 2-5 and resulting in a premature stop codon. The pathogenic effect of this duplication was confirmed by a cDNA analysis and functional assays. The identification of microhomology flanking the breakpoint site suggests a possible underlying mechanism.
Published: 2017
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47. AMPA-receptor specific biogenesis complexes control synaptic transmission and intellectual ability

Author: Gerd Zolles, Laurence Colleaux, Nouriya Al-Sannaa, Christine Bole-Feysot, Uwe Schulte, Rami Abou Jamra, Sami Boudkkazi, Jochen Schwenk, Abdelkrim Saadi, Irene Schaber, Patrick Nitschké, Karine Siquier-Pernet, Heinrich Sticht, Wolfgang Bildl, Akos Kulik, Aline Brechet, Bernd Fakler, Rebecca Buchert, Arndt Rolfs, André Reis, Unité de Neurobiologie des canaux Ioniques et de la Synapse (UNIS - Inserm U1072), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Bioinformatik, Institut für Biochemie, Albrecht-Kossel-Institut fur Neuroregeneration, Universität Rostock, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Human Genetics, Rheinische Friedrich-Wilhelms-Universität Bonn, Molecular Biology of Cochlear Neurotransmission Junior Research Group, Dept of Otolaryngology, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institute of Human Genetics [Erlangen]
Subjects: 0301 basic medicine, Male, Proteomics, Science, General Physics and Astronomy, Nerve Tissue Proteins, AMPA receptor, Neurotransmission, Biology, Endoplasmic Reticulum, Synaptic Transmission, General Biochemistry, Genetics and Molecular Biology, Article, Chromatography, Affinity, Mass Spectrometry, 03 medical and health sciences, Mice, 0302 clinical medicine, Intellectual Disability, Animals, Humans, Receptors, AMPA, Microscopy, Immunoelectron, Gene, Alleles, Multidisciplinary, Carnitine O-Palmitoyltransferase, Endoplasmic reticulum, musculoskeletal, neural, and ocular physiology, Cell Membrane, Glutamate receptor, Brain, Membrane Proteins, General Chemistry, Cell biology, Pedigree, Rats, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, nervous system, Proteome, Mutation, Excitatory postsynaptic potential, Female, 030217 neurology & neurosurgery, Biogenesis
Abstract: AMPA-type glutamate receptors (AMPARs), key elements in excitatory neurotransmission in the brain, are macromolecular complexes whose properties and cellular functions are determined by the co-assembled constituents of their proteome. Here we identify AMPAR complexes that transiently form in the endoplasmic reticulum (ER) and lack the core-subunits typical for AMPARs in the plasma membrane. Central components of these ER AMPARs are the proteome constituents FRRS1l (C9orf4) and CPT1c that specifically and cooperatively bind to the pore-forming GluA1-4 proteins of AMPARs. Bi-allelic mutations in the human FRRS1L gene are shown to cause severe intellectual disability with cognitive impairment, speech delay and epileptic activity. Virus-directed deletion or overexpression of FRRS1l strongly impact synaptic transmission in adult rat brain by decreasing or increasing the number of AMPARs in synapses and extra-synaptic sites. Our results provide insight into the early biogenesis of AMPARs and demonstrate its pronounced impact on synaptic transmission and brain function., The biogenesis of AMPA-type glutamate receptor (AMPAR) complexes is only partially understood. Here the authors identify transient assemblies of GluA1-4 proteins and proteins FRRS1l/CPT1c that drive formation of mature AMPAR complexes in the ER. Mutations in FRRS1l are associated with intellectual disability and epilepsy in three families.
Published: 2017
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48. Mutations in MAPKBP1 Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis

Author: André Paget, Philippe Nicoud, Charline Henry, Emilie Filhol, Sabine Leh, Fan Yang, Flora Silbermann, Jan Halbritter, Alexandre Benmerah, Arthur Gutter, Friedhelm Hildebrandt, Per M. Knappskog, Anne E.C. Mellgren, Heon Yung Gee, Richard Sandford, Cecilie Bredrup, Dominique Joly, Pauline Krug, Helge Boman, Sophie Saunier, Christine Bole-Feysot, Nurcan Cengiz, Heidi Haugland, Maxence S. Macia, Marion Delous, Damien Brackmann, Nayir Ahmet, Eyvind Rødahl, Andreas W. Sailer, Edward J. Oakeley, Bolan Linghu, Daniela A. Braun, Stefan Johansson, Albane A. Bizet, Patrick Nitschke, Pierre Saint Mézard, Laboratoire des Maladies Rénales Héréditaires, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Harvard Medical School [Boston] (HMS), Universitätsklinikum Leipzig [Germany] (UKL), Haukeland University Hospital, University of Bergen (UiB), Molecular bases of hereditary kidney diseases: nephronophthisis and hypodysplasia (Equipe Inserm U1163), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpitaux du Pays du Mont-Blanc, Førde Central Hospital [Førde, Norway] (FCH), Istanbul University, University of Cambridge [UK] (CAM), Baskent University, Novartis Institutes for Biomedical Research [Cambridge, MA, USA], Novartis Institutes for BioMedical Research (NIBR), and Benmerah, Alexandre
Subjects: 0301 basic medicine, Candidate gene, 030232 urology & nephrology, Cell Cycle Proteins, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030105 genetics & heredity, MAPKBP1, Kidney, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Mice, 0302 clinical medicine, Spindle Poles, Child, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), Zebrafish, Genetics, Mice, Knockout, Cilium, Intracellular Signaling Peptides and Proteins, Kidney Diseases, Cystic, Phenotype, Pedigree, mitotic spindle, Signal Transduction, Adolescent, Mitosis, Late onset, Nerve Tissue Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, Young Adult, Nephronophthisis, retinitis pigmentosa, Ciliogenesis, Report, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Retinitis pigmentosa, medicine, Juvenile, Animals, Humans, digenism, Cilia, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Gene, Alleles, WDR62, [SDV.GEN]Life Sciences [q-bio]/Genetics, Correction, Fibroblasts, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Fibrosis, Human genetics, Ciliopathy, Disease Models, Animal, ciliopathy, 030104 developmental biology, Gene Expression Regulation, nephronophthisis, Mutation, NIH 3T3 Cells, Kidney Failure, Chronic, MAP kinase, 030217 neurology & neurosurgery, DNA Damage
Abstract: International audience; Nephronophthisis (NPH), an autosomal-recessive tubulointerstitial nephritis, is the most common cause of hereditary end-stage renal disease in the first three decades of life. Since most NPH gene products (NPHP) function at the primary cilium, NPH is classified as a ciliopathy. We identified mutations in a candidate gene in eight individuals from five families presenting late-onset NPH with massive renal fibrosis. This gene encodes MAPKBP1, a poorly characterized scaffolding protein for JNK signaling. Immunofluorescence analyses showed that MAPKBP1 is not present at the primary cilium and that fibroblasts from affected individuals did not display ciliogenesis defects, indicating that MAPKBP1 may represent a new family of NPHP not involved in cilia-associated functions. Instead, MAPKBP1 is recruited to mitotic spindle poles (MSPs) during the early phases of mitosis where it colocalizes with its paralog WDR62, which plays a key role at MSP. Detected mutations compromise recruitment of MAPKBP1 to the MSP and/or its interaction with JNK2 or WDR62. Additionally, we show increased DNA damage response signaling in fibroblasts from affected individuals and upon knockdown of Mapkbp1 in murine cell lines, a phenotype previously associated with NPH. In conclusion, we identified mutations in MAPKBP1 as a genetic cause of juvenile or late-onset and cilia-independent NPH.
Published: 2017
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49. WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells

Author: Laurent Bidat, Alice Kuster, Patrick Nitschké, Jamel Chelly, Stanislas Lyonnet, Séverine Drunat, Alexandre D Baffet, Melanie Jenneson-Liver, Alain Verloes, Jacques Motte, Thomas Besnard, Maria A. Rujano, Nathalie Bednarek, Benjamin Cogné, Daniel Medina-Cano, Tania Attié-Bitach, Christine Bole, Camille Maillard, Antoinette Gelot, Sandrine Passemard, Vincent Cantagrel, Karine Poirier, Nathalie Boddaert, Nadia Bahi-Buisson, Mara Cavallin, Martine Doco-Fenzy, Claire Beneteau, Sophie Thomas, Matias Simons, Meriem Garfa-Traore, Marlène Rio, M Louise Reilly, Jelena Martinovic, Marion Eveillard, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre hospitalier universitaire de Nantes (CHU Nantes), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), Centre National de la Recherche Scientifique (CNRS), Sorbonne Universités (COMUE), Université Paris Diderot - Paris 7 (UPD7), Hôpital Antoine Béclère, Assistance Publique - Hôpitaux de Paris (AP-HP), Centre Hospitalier René Dubos [Pontoise], Hôpital Maison Blanche, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], ProdInra, Migration, and Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)
Subjects: 0301 basic medicine, Male, Microcephaly, Mitotic index, Pontocerebellar hypoplasia, Lissencephaly, Mitosis, Nerve Tissue Proteins, Biology, Animals, Genetically Modified, 03 medical and health sciences, Young Adult, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Neural Stem Cells, medicine, Animals, Drosophila Proteins, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], microcephaly, Exome sequencing, Cells, Cultured, Genetics, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Cerebellar ataxia, Brain, ponto-cerebellar hypoplasia, Fibroblasts, medicine.disease, WDR81, 030104 developmental biology, Ki-67 Antigen, Gene Expression Regulation, Child, Preschool, Mutation, Cancer research, Cerebellar atrophy, Drosophila, Female, RNA Interference, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), medicine.symptom, microlissencephaly
Abstract: International audience; Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors. Despite the recent identification of six genes involved in microlissencephaly, the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. Patient phenotypes ranged from severe microcephaly with extremely reduced gyration with pontocerebellar hypoplasia to moderate microcephaly with cerebellar atrophy. In patient fibroblast cells, WDR81 mutations were associated with increased mitotic index and delayed prometaphase/metaphase transition. Similarly, in vivo, we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans.
Published: 2017
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50. De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Author: Duangrurdee Wattanasirichaigoon, Frédérique Magdinier, Axel M. Hillmer, Mung Kei Kong, Sabine Sigaudy, Myriam Oufadem, Hicham Filali, Hülya Kayserili, Christopher T. Gordon, Denise Williams, Peter Nürnberg, Carine Bonnard, Stanislas Lyonnet, Camille Dion, Siham Chafai Elalaoui, Jeanne Amiel, Audrey S.M. Teo, Nobuhiko Okamoto, Bruno Reversade, Asif Javed, Dieter Meschede, Alex Magee, Abdelaziz Sefiani, Rachel E A Irving, Alexandra D. Gurzau, James M. Murphy, Nicola K. Ragge, Bernd Wollnik, Gökhan Tunçbilek, Koh-ichiro Yoshiura, Chalermpong Chatdokmaiprai, Tamara Beck, Hallvard Reigstad, Christine Bole-Feysot, Kelan Chen, Nicolas Lévy, Michael L. Cunningham, Nadine Rosin, Ruth McGowan, Holger Thiele, Janine Altmüller, Vinod Varghese, Nawfal Fejjal, Patrick Nitschké, Ilham Ratbi, Marnie E. Blewitt, Gökhan Yigit, Wolfgang Mühlbauer, Meriem Fikri, Shifeng Xue, S Faisal Ahmed, Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Department of Clinical Genetics, Leicester Royal Infirmary, Universität zu Köln, Génétique Médicale et Génomique Fonctionnelle ( GMGF ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Plate Forme Paris Descartes de Bioinformatique ( BIP-D ), Université Paris Descartes - Paris 5 ( UPD5 ), Department of Medical Genetics, Istanbul University, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), ACS - Amsterdam Cardiovascular Sciences, ARD - Amsterdam Reproduction and Development, Center for Reproductive Medicine, ACS - Heart failure & arrhythmias, ACS - Diabetes & metabolism, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nagasaki University, University Hospitals Leicester-University Hospitals Leicester, Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Universität zu Köln = University of Cologne, and Roche, Stephane
Subjects: Male, 0301 basic medicine, MESH : Cell Line, Embryology, Chromosomal Proteins, Non-Histone, Xenopus, MESH : Child, Preschool, medicine.disease_cause, Epigenesis, Genetic, MESH: Choanal Atresia, MESH : Microphthalmos, Mice, Xenopus laevis, 0302 clinical medicine, MESH : Xenopus laevis, Microphthalmos, Facioscapulohumeral muscular dystrophy, Missense mutation, MESH: Animals, MESH : Female, MESH: Epigenesis, Genetic, MESH : Epigenesis, Genetic, Muscular dystrophy, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, nasal development, Genetics, Mutation, biology, Medical genetics, MESH: Genetic Predisposition to Disease, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, MESH: Nose, food and beverages, Muscular Dystrophy, Facioscapulohumeral, 3. Good health, MESH : Muscular Dystrophy, Facioscapulohumeral, Genetic linkage study, Child, Preschool, MESH : Choanal Atresia, Female, Epigenetics, MESH : Nose, MESH : Chromosomal Proteins, Non-Histone, medicine.medical_specialty, MESH: Microphthalmos, MESH : Male, Mutation, Missense, MESH: Muscular Dystrophy, Facioscapulohumeral, MESH : Mice, Inbred C57BL, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Nose, Choanal Atresia, Cell Line, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH: Xenopus laevis, MESH: Chromosomal Proteins, Non-Histone, MESH : Mice, medicine, Bosma arhinia microphthalmia syndrome, Animals, Humans, Genetic Predisposition to Disease, Allele, MESH: Mice, MESH: Mutation, Missense, FSHD, MESH: Humans, SMCHD1, MESH: Child, Preschool, MESH : Humans, medicine.disease, biology.organism_classification, MESH: Male, MESH: Cell Line, Mice, Inbred C57BL, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [ SDV.BDD.EO ] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, MESH : Genetic Predisposition to Disease, MESH : Animals, MESH: Female, 030217 neurology & neurosurgery, MESH : Mutation, Missense
Abstract: International audience; Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD.
Published: 2017
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