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1. Inhibition of poly(ADP-Ribosyl)ation reduced vascular smooth muscle cells loss and improves aortic disease in a mouse model of human accelerated aging syndrome

Author

Déborah Cardoso, Solenn Guilbert, Philippe Guigue, Aurélie Carabalona, Karim Harhouri, Cécile Peccate, Johana Tournois, Zoheir Guesmia, Lino Ferreira, Catherine Bartoli, Nicolas Levy, Laurence Colleaux, Xavier Nissan, and Antoine Muchir

Subjects
Cytology, QH573-671
Abstract

Abstract Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder associated with features of accelerated aging. HGPS is an autosomal dominant disease caused by a de novo mutation of LMNA gene, encoding A-type lamins, resulting in the truncated form of pre-lamin A called progerin. While asymptomatic at birth, patients develop symptoms within the first year of life when they begin to display accelerated aging and suffer from growth retardation, and severe cardiovascular complications including loss of vascular smooth muscle cells (VSMCs). Recent works reported the loss of VSMCs as a major factor triggering atherosclerosis in HGPS. Here, we investigated the mechanisms by which progerin expression leads to massive VSMCs loss. Using aorta tissue and primary cultures of murine VSMCs from a mouse model of HGPS, we showed increased VSMCs death associated with increased poly(ADP-Ribosyl)ation. Poly(ADP-Ribosyl)ation is recognized as a post-translational protein modification that coordinates the repair at DNA damage sites. Poly-ADP-ribose polymerase (PARP) catalyzes protein poly(ADP-Ribosyl)ation by utilizing nicotinamide adenine dinucleotide (NAD+). Our results provided the first demonstration linking progerin accumulation, augmented poly(ADP-Ribosyl)ation and decreased nicotinamide adenine dinucleotide (NAD+) level in VSMCs. Using high-throughput screening on VSMCs differentiated from iPSCs from HGPS patients, we identified a new compound, trifluridine able to increase NAD+ levels through decrease of PARP-1 activity. Lastly, we demonstrate that trifluridine treatment in vivo was able to alleviate aortic VSMCs loss and clinical sign of progeria, suggesting a novel therapeutic approach of cardiovascular disease in progeria.

Published
2024
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2. Between hope and reality: treatment of genetic diseases through nucleic acid-based drugs

Author

Virginie Baylot, Thi Khanh Le, David Taïeb, Palma Rocchi, and Laurence Colleaux

Subjects
Biology (General), QH301-705.5
Abstract

Abstract Rare diseases (RD) affect a small number of people compared to the general population and are mostly genetic in origin. The first clinical signs often appear at birth or in childhood, and patients endure high levels of pain and progressive loss of autonomy frequently associated with short life expectancy. Until recently, the low prevalence of RD and the gatekeeping delay in their diagnosis have long hampered research. The era of nucleic acid (NA)-based therapies has revolutionized the landscape of RD treatment and new hopes arise with the perspectives of disease-modifying drugs development as some NA-based therapies are now entering the clinical stage. Herein, we review NA-based drugs that were approved and are currently under investigation for the treatment of RD. We also discuss the recent structural improvements of NA-based therapeutics and delivery system, which overcome the main limitations in their market expansion and the current approaches that are developed to address the endosomal escape issue. We finally open the discussion on the ethical and societal issues that raise this new technology in terms of regulatory approval and sustainability of production.

Published
2024
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3. INTS13 variants causing a recessive developmental ciliopathy disrupt assembly of the Integrator complex

Author

Lauren G. Mascibroda, Mohammad Shboul, Nathan D. Elrod, Laurence Colleaux, Hanan Hamamy, Kai-Lieh Huang, Natoya Peart, Moirangthem Kiran Singh, Hane Lee, Barry Merriman, Jeanne N. Jodoin, Poojitha Sitaram, Laura A. Lee, Raja Fathalla, Baeth Al-Rawashdeh, Osama Ababneh, Mohammad El-Khateeb, Nathalie Escande-Beillard, Stanley F. Nelson, Yixuan Wu, Liang Tong, Linda J. Kenney, Sudipto Roy, William K. Russell, Jeanne Amiel, Bruno Reversade, and Eric J. Wagner

Subjects
Science
Abstract

The integrator complex is required for the synthesis of protein coding and non-coding RNA and contains the protein INTS13. Here, the authors find germline mutations in INTS13 in two families with oral facial digital syndrome and show that the mutation affects the c-terminal domain of the protein and disrupts cilliogenesis.

Published
2022
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4. 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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5. Loss of the neurodevelopmental disease-associated gene miR-146a impairs neural progenitor differentiation and causes learning and memory deficits

Author

Julien Fregeac, Stéphanie Moriceau, Antoine Poli, Lam Son Nguyen, Franck Oury, and Laurence Colleaux

Subjects
Neurodevelopmental disorders, MicroRNA, miR-146a, Neurodevelopment, Neural stem cells differentiation, Hippocampus-dependent cognitive functions, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Formation and maintenance of appropriate neural networks require tight regulation of neural stem cell proliferation, differentiation, and neurogenesis. microRNAs (miRNAs) play an important role in brain development and plasticity, and dysregulated miRNA profiles have been linked to neurodevelopmental disorders including autism, schizophrenia, or intellectual disability. Yet, the functional role of miRNAs in neural development and postnatal brain functions remains unclear. Methods Using a combination of cell biology techniques as well as behavioral studies and brain imaging, we characterize mouse models with either constitutive inactivation or selectively hippocampal knockdown of the neurodevelopmental disease-associated gene Mir146a, the most commonly deregulated miRNA in developmental brain disorders (DBD). Results We first show that during development, loss of miR-146a impairs the differentiation of radial glial cells, neurogenesis process, and neurite extension. In the mouse adult brain, loss of miR-146a correlates with an increased hippocampal asymmetry coupled with defects in spatial learning and memory performances. Moreover, selective hippocampal downregulation of miR-146a in adult mice causes severe hippocampal-dependent memory impairments indicating for the first time a role for this miRNA in postnatal brain functions. Conclusion Our results show that miR-146a expression is critical for correct differentiation of neural stem cell during brain development and provide for the first time a strong argument for a postnatal role of miR-146a in regulating hippocampal-dependent memory. Furthermore, the demonstration that the Mir146a −/− mouse recapitulates several aspects reported in DBD patients, including impaired neurogenesis, abnormal brain anatomy, and working and spatial memories deficits, provides convincing evidence that the dysregulation of miR146a contributes to the pathogenesis of DBDs.

Published
2020
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6. 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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7. 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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8. High N-glycan multiplicity is critical for neuronal adhesion and sensitizes the developing cerebellum to N-glycosylation defect

Author

Daniel Medina-Cano, Ekin Ucuncu, Lam Son Nguyen, Michael Nicouleau, Joanna Lipecka, Jean-Charles Bizot, Christian Thiel, François Foulquier, Nathalie Lefort, Catherine Faivre-Sarrailh, Laurence Colleaux, Ida Chiara Guerrera, and Vincent Cantagrel

Subjects
N-glycosylation, congenital disorders of glycosylation, neuronal migration, cell adhesion, cerebellum, proteomics, Medicine, Science, Biology (General), QH301-705.5
Abstract

Proper brain development relies highly on protein N-glycosylation to sustain neuronal migration, axon guidance and synaptic physiology. Impairing the N-glycosylation pathway at early steps produces broad neurological symptoms identified in congenital disorders of glycosylation. However, little is known about the molecular mechanisms underlying these defects. We generated a cerebellum specific knockout mouse for Srd5a3, a gene involved in the initiation of N-glycosylation. In addition to motor coordination defects and abnormal granule cell development, Srd5a3 deletion causes mild N-glycosylation impairment without significantly altering ER homeostasis. Using proteomic approaches, we identified that Srd5a3 loss affects a subset of glycoproteins with high N-glycans multiplicity per protein and decreased protein abundance or N-glycosylation level. As IgSF-CAM adhesion proteins are critical for neuron adhesion and highly N-glycosylated, we observed impaired IgSF-CAM-mediated neurite outgrowth and axon guidance in Srd5a3 mutant cerebellum. Our results link high N-glycan multiplicity to fine-tuned neural cell adhesion during mammalian brain development.

Published
2018
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9. Human Slack Potassium Channel Mutations Increase Positive Cooperativity between Individual Channels

Author

Grace E. Kim, Jack Kronengold, Giulia Barcia, Imran H. Quraishi, Hilary C. Martin, Edward Blair, Jenny C. Taylor, Olivier Dulac, Laurence Colleaux, Rima Nabbout, and Leonard K. Kaczmarek

Subjects
Biology (General), QH301-705.5
Abstract

Summary: Disease-causing mutations in ion channels generally alter intrinsic gating properties such as activation, inactivation, and voltage dependence. We examined nine different mutations of the KCNT1 (Slack) Na+-activated K+ channel that give rise to three distinct forms of epilepsy. All produced many-fold increases in current amplitude compared to the wild-type channel. This could not be accounted for by increases in the intrinsic open probability of individual channels. Rather, greatly increased opening was a consequence of cooperative interactions between multiple channels in a patch. The degree of cooperative gating was much greater for all of the mutant channels than for the wild-type channel, and could explain increases in current even in a mutant with reduced unitary conductance. We also found that the same mutation gave rise to different forms of epilepsy in different individuals. Our findings indicate that a major consequence of these mutations is to alter channel-channel interactions. : Slack KCNT1 channels regulate how neurons respond to sustained stimulation. Kim et al. characterized nine KCNT1 mutations found in epilepsy patients with severe intellectual disabilities and showed that, in isolation, channel behavior is unaltered. However, in groups, mutant channels interact with each other abnormally, increasing current that flows through the channels.

Published
2014
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10. MYT1L-associated neurodevelopmental disorder: description of 40 new cases and literature review of clinical and molecular aspects

Author

James W. Wheless, Thierry Frebourg, Robert Olaso, Rosemarie Smith, Kelly Nori, François Lecoquierre, Delphine Héron, Roseline Caumes, Anne Boland, Ange-Line Bruel, Candy Kumps, Gaël Nicolas, Sarah Stewart, Sophie Rondeau, Diane Doummar, Marlène Rio, Giulia Barcia, Anne-Marie Guerrot, Gwenaël Le Guyader, Alexandra Afenjar, Sarah Vergult, Karine Poirier, Juliette Coursimault, Jennifer Morrison, Amy Kritzer, Anne-Sophie Alaix, Rebecca Hernan, Anne-Sophie Denommé-Pichon, Sabine Sigaudy, Christine Coubes, Pascale Saugier-Veber, Francisca Millan Zamora, Austin Larson, Michelle M. Morrow, Christine Poitou, Björn Menten, Mathilde Nizon, Thomas Smol, Elise Schaefer, Bénédicte Gérard, Charles Coutton, Salima El Chehadeh, Fanggeng Zou, Stéphanie Valence, Anita Shanmugham, Wendy K. Chung, Bert Callewaert, Christina Kresge, Arnold Munnich, Beth A. Pletcher, Laurence Faivre, Estelle Colin, Laurence Colleaux, Patricia G Wheeler, Annelies Dheedene, Frédéric Tran Mau-Them, Jean-François Deleuze, Claude Houdayer, Jeanne Amiel, Frédéric Bilan, Marine Tessarech, Bertrand Isidor, Guillaume Jouret, Cyril Mignot, Benjamin Cogné, Shuxi Liu, Boris Keren, Françoise Devillard, Catherine Schramm, Margaret Helm, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), GeneDx [Gaithersburg, MD, USA], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut de génétique médicale d’Alsace, Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Sorbonne Université (SU), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Grenoble, 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 Paris Cité (UPCité), 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), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ghent University Hospital, Columbia University Irving Medical Center (CUIMC), University of Colorado Anschutz [Aurora], University of Tennessee System, Rutgers New Jersey Medical School (NJMS), Rutgers University System (Rutgers), Université de Lille, Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Maine Medical Center, Arnold Palmer Hospital, Boston Children's Hospital, National Center of Genetics, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)

Subjects
Male, Bioinformatics, Epilepsy, 0302 clinical medicine, Neurodevelopmental disorder, MESH: Child, Intellectual disability, Missense mutation, MESH: Obesity, MESH: Genetic Variation, MESH: Nerve Tissue Proteins, Child, Genetics (clinical), MESH: Genetic Association Studies, MESH: Heterozygote, 0303 health sciences, MESH: Transcription Factors, MESH: Infant, 3. Good health, Phenotype, MESH: Feeding and Eating Disorders, MESH: Young Adult, Child, Preschool, MESH: Epilepsy, Learning disability, Female, medicine.symptom, Adult, Heterozygote, Adolescent, Language delay, Nerve Tissue Proteins, Biology, MESH: Phenotype, MESH: Language Development Disorders, Feeding and Eating Disorders, Young Adult, 03 medical and health sciences, Genetics, medicine, Humans, Language Development Disorders, Obesity, Genetic Association Studies, 030304 developmental biology, MESH: Neurodevelopmental Disorders, MESH: Adolescent, MESH: Humans, MESH: Child, Preschool, Genetic Variation, Infant, MESH: Adult, medicine.disease, Human genetics, MESH: Male, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, Autism, MESH: Female, 030217 neurology & neurosurgery, Transcription Factors
Abstract

International audience; Pathogenic variants of the myelin transcription factor-1 like (MYT1L) gene include heterozygous missense, truncating variants and 2p25.3 microdeletions and cause a syndromic neurodevelopmental disorder (OMIM#616,521). Despite enrichment in de novo mutations in several developmental disorders and autism studies, the data on clinical characteristics and genotype-phenotype correlations are scarce, with only 22 patients with single nucleotide pathogenic variants reported. We aimed to further characterize this disorder at both the clinical and molecular levels by gathering a large series of patients with MYT1L-associated neurodevelopmental disorder. We collected genetic information on 40 unreported patients with likely pathogenic/pathogenic MYT1L variants and performed a comprehensive review of published data (total = 62 patients). We confirm that the main phenotypic features of the MYT1L-related disorder are developmental delay with language delay (95%), intellectual disability (ID, 70%), overweight or obesity (58%), behavioral disorders (98%) and epilepsy (23%). We highlight novel clinical characteristics, such as learning disabilities without ID (30%) and feeding difficulties during infancy (18%). We further describe the varied dysmorphic features (67%) and present the changes in weight over time of 27 patients. We show that patients harboring highly clustered missense variants in the 2-3-ZNF domains are not clinically distinguishable from patients with truncating variants. We provide an updated overview of clinical and genetic data of the MYT1L-associated neurodevelopmental disorder, hence improving diagnosis and clinical management of these patients.

Published
2022

12. MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia

Author

Nathalie Rabasse, Catherine Fossoud, Nadia Bahi-Buisson, Miranda S. C. Wilson, Elsa Lorino, Celine Banal, Meral Topçu, Gaele Pitelet, Eric Bieth, Christine Bole-Feysot, Nami Altin, Vincent Cantagrel, Arnold Munnich, Marie-Therese Vasilache-Dangles, Fabienne Giuliano, Lydie Burglen, Adolfo Saiardi, Valentina Stanley, Nathalie Lefort, Giulia Barcia, Pierre David, Karthyayani Rajamani, Daniel Medina-Cano, Patrick Nitschke, Joseph G. Gleeson, Maha S. Zaki, Laurence Colleaux, Nathalie Boddaert, Fatma Mujgan Sonmez, Damir Musaev, Ekin Ucuncu, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University College of London [London] (UCL), 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 Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Antibes - Juan-les-Pins, CHU Toulouse [Toulouse], Hacettepe University = Hacettepe Üniversitesi, Karadeniz Technical University (KTU), Rady Children's Hospital, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Gestionnaire, Hal Sorbonne Université

Subjects
Male, 0301 basic medicine, Cytoplasm, [SDV]Life Sciences [q-bio], Cellular differentiation, General Physics and Astronomy, Gene Knockout Techniques, chemistry.chemical_compound, 0302 clinical medicine, Homeostasis, Inositol, Phosphorylation, Child, Chelating Agents, Mice, Knockout, Multidisciplinary, Cell Death, Chemistry, Stem Cells, Neurodevelopmental disorders, Cell Differentiation, Cell biology, [SDV] Life Sciences [q-bio], Child, Preschool, Second messenger system, Female, Intracellular, Cell physiology, Programmed cell death, Phytic Acid, Science, Pontocerebellar hypoplasia, Stem-cell differentiation, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Cerebellar Diseases, medicine, Animals, Humans, HEK 293 cells, Infant, General Chemistry, medicine.disease, Phosphoric Monoester Hydrolases, Mice, Inbred C57BL, HEK293 Cells, 030104 developmental biology, Mutation, Transcriptome, 030217 neurology & neurosurgery
Abstract

Inositol polyphosphates are vital metabolic and secondary messengers, involved in diverse cellular functions. Therefore, tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, we describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the multiple inositol-polyphosphate phosphatase 1 gene (MINPP1). Patients are found to have a distinct type of Pontocerebellar Hypoplasia with typical basal ganglia involvement on neuroimaging. We find that patient-derived and genome edited MINPP1−/− induced stem cells exhibit an inefficient neuronal differentiation combined with an increased cell death. MINPP1 deficiency results in an intracellular imbalance of the inositol polyphosphate metabolism. This metabolic defect is characterized by an accumulation of highly phosphorylated inositols, mostly inositol hexakisphosphate (IP6), detected in HEK293 cells, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions. These data suggest the involvement of IP6-mediated chelation on Pontocerebellar Hypoplasia disease pathology and thereby highlight the critical role of MINPP1 in the regulation of human brain development and homeostasis., 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

13. Macrocéphalie et leucodystrophie : à propos de 3 cas

Author

Wahiba Amer El Khedoud, Nora Kassouri, Lamine Moussa, Abdelkrim Saadi, Gazzero Elisabetta, Saadia Lougani, Laurence Colleaux, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
03 medical and health sciences, 0302 clinical medicine, Neurology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030212 general & internal medicine, Neurology (clinical), 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 3. Good health
Abstract

Introduction La macrocephalie associee a une deficience intellectuelle avec ou sans anomalies cerebrales peut etre revelatrice de nombreuses pathologies neurogenetique chez l’enfant. A ce jour on denombre environ une trentaine de genes sans compter les anomalies chromosomiques. Observation Nous rapportons l’etude clinique, radiologique et genetique d’une famille et 2 cas isoles : – Une famille consanguine composee de 4 patients presentant un retard developpement psychomoteur, tetraparesie,epilepsie, macrocephalie et leucodystrophie kystique a l’IRM en rapport avec une mutation homozygote du site donneur d’epissage (c.423 + 1 g > a) de l’exon 5 du gene MLC1,megalencephalie leucodystrophie avec kystique sous corticaux – Un enfant âge de 3 ans presentant un leger deficit intellectuel, cataracte congenitale, nystagmus multidirectionnel, tetraparesie spastique,macrocephalie et hypomyelinisation cerebrale due a une mutation homozygote c.414 + 1 G > T de l’exon 5 du gene FAM126A en faveur du syndrome d’hypomyelinisation-cataracte congenitale. – Un nourrisson de 12 mois qui presente un retard developpement moteur, macrocephalie (+ 3DS), front large et bombe, nystagmus congenital, palais ogival, hypotonie axiale, hypertonie segmentaire et leucodystrophie avec un pic marque de NAA a la spectro-IRM en faveur de la maladie de Canavan. Discussion La macrocephalie est un bon signe d’orientation diagnostique devant une deficience intellectuelle avec leucodystrophie. On la retrouve dans la maladie d’Alexander, Canavan, megalencephalie leucodystrophie avec kystique sous corticaux 1 et 2, L2- hydroxy glutaric aciduria. Alors qu’elle n’a jamais ete rapportee dans les 15 syndromes d’hypomyelinisation et notamment la quinzaine de cas d’hypomyelinisation cataracte lies au gene FAM126A. Conclusion L’association macrocephalie, deficit intellectuel,leucodystrophie permet d’evoquer certains diagnostics et d’orienter l’analyse moleculaire.

Published
2020

14. INTS13Mutations Causing a Developmental Ciliopathy Disrupt Integrator Complex Assembly

Author

Barry Merriman, Lauren G. Mascibroda, Laurence Colleaux, Yixuan Wu, Singh Mk, Osama H. Ababneh, Al-Rawashdeh B, Jeanne N. Jodoin, Nathalie Escande-Beillard, Stan F. Nelson, Kai Huang, Hanan Hamamy, Natoya Peart, Bruno Reversade, Eric J. Wagner, El-Khateeb M, Hang Lee, Nathan D. Elrod, Laura A. Lee, William K. Russell, Mohammad Shboul, Amiel J, Linda J. Kenney, Fathalla R, and Liang Tong

Subjects
Genetics, Ciliopathy, Germline mutation, Integrator complex, Ciliogenesis, Motile cilium, medicine, Biology, medicine.disease, Disease gene identification, Ciliopathies, Germline
Abstract

Oral-facial-digital syndromes (OFD) are a heterogeneous group of congenital disorders characterized by malformations of the face and oral cavity, and digit anomalies. To date, mutations in 12 ciliary-related genes have been identified that cause several types of OFD, suggesting that OFDs constitute a subgroup of developmental ciliopathies. Through homozygosity mapping and exome sequencing of two families with variable OFD type 2, we identified distinct germline mutations inINTS13, a subunit of the Integrator complex. This 14-component complex associates with RNAPII and can cleave nascent RNA to modulate gene expression. We determined that INTS13 utilizes a discrete domain within its C-terminus to bind the Integrator cleavage module, which is disrupted by the identified germlineINTS13mutations. Depletion ofINTS13disrupts ciliogenesis in human cultured cells and causes dysregulation of a broad collection of ciliary genes. Accordingly, its knockdown inXenopusembryos lead to motile cilia anomalies. Altogether, we show that mutations inINTS13cause an autosomal recessive ciliopathy, which reveals key interactions within Integrator components.

Published
2020

15. MINPP1prevents intracellular accumulation of the cation chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia

Author

Arnold Munnich, Catherine Fossoud, Nathalie Lefort, Meral Topçu, Patrick Nitschke, Pierre David, Karthyayani Rajamani, Joseph G. Gleeson, Christine Bole-Feysot, Marie-Therese Vasilache-Dangles, Valentina Stanley, Nadia Bahi-Buisson, Miranda S. C. Wilson, Laurence Colleaux, Elsa Lorino, Nathalie Rabasse, Lydie Burglen, Gaele Pitelet, Adolfo Saiardi, Maha S. Zaki, Nami Altin, Fabienne Giuliano, Vincent Cantagrel, Giulia Barcia, Eric Bieth, Daniel Medina-Cano, Fatma Mujgan Sonmez, Damir Musaev, Nathalie Boddaert, and Ekin Ucuncu

Subjects
Cell physiology, chemistry.chemical_compound, chemistry, HEK 293 cells, Second messenger system, Pontocerebellar hypoplasia, medicine, Inositol, medicine.disease, Multiple inositol-polyphosphate phosphatase 1, Intracellular, Homeostasis, Cell biology
Abstract

Inositol polyphosphates are vital metabolic and secondary messengers, involved in diverse cellular functions. Therefore, tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, we describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in themultiple inositol polyphosphate phosphatase 1gene (MINPP1). Patients were found to have a distinct type of Pontocerebellar Hypoplasia with typical basal ganglia involvement on neuroimaging. We found that patient-derived and genome editedMINPP1-/-induced pluripotent stem cells (iPSCs) are not able to differentiate efficiently into neurons. MINPP1 deficiency results in an intracellular imbalance of the inositol polyphosphate metabolism. This metabolic defect is characterized by an accumulation of highly phosphorylated inositols, mostly inositol hexakiphosphate (IP6), detected in HEK293, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions. These data suggest the involvement of IP6-mediated chelation on Pontocerebellar Hypoplasia disease pathology and thereby highlight the critical role of MINPP1 in the regulation of human brain development and homeostasis.

Published
2020

16. Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia

Author

Andrea Bevot, Diana Chiang, Laurence Colleaux, Christian A. Hübner, Hans Hartmann, Zhao-Qi Wang, Tobias B. Haack, Ralf A. Husain, J. Christopher Hennings, Kevin Rostasy, Michael C. Kruer, Hossein Darvish, Olaf Riess, Andy Cheuk Him Ng, Marion Döbler-Neumann, Tim M. Strom, Lucia Laugwitz, Johannes A. Mayr, Thomas Klopstock, Xenia Kobeleva, René G. Feichtinger, Saghar Ghasemi Firouzabadi, Rebecca Buchert, Amelie J. Müller, Matias Wagner, Antje K. Huebner, Shrikant Mane, Marcus Deschauer, Ingeborg Krägeloh-Mann, Abdelkrim Saadi, Ulrich Brandl, Penelope E. Bonnen, Christian Marx, Isabell Cordts, Thomas Klockgether, Abbas Tafakhori, Thomas Meitinger, Florentine Radelfahr, Arnaud Besse, Mona Grimmel, Marc Sturm, Saskia B. Wortmann, Somayeh Bakhtiari, Francois V. Bolduc, Stefanie Beck-Woedl, Thomas Nägele, 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), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Jena University Hospital [Jena], University of Tübingen, Helmholtz-Zentrum München (HZM), Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Leibniz Association, Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Université d'Alger 1 (Benyoucef Benkhedda), Universität Witten Herdecke, German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), University Children's Hospital of Tübingen, Partenaires INRAE, Hannover Medical School [Hannover] (MHH), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Technische Universität München [München] (TUM), University of Bonn, Semnan University, University of Arizona, Baylor College of Medicine (BCM), Baylor University, University of Alberta, Tehran University of Medical Sciences (TUMS), Yale University School of Medicine, University of Social Welfare and Rehabilitation Sciences [Tehran], Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany], Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität München [München] (TUM)-Ludwig-Maximilians-Universität München (LMU), Amalia Children’s Hospital [Nijmegen, The Netherlands], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), Helmholtz Zentrum München = German Research Center for Environmental Health, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Yale School of Medicine [New Haven, Connecticut] (YSM), and COLLEAUX, Laurence

Subjects
0301 basic medicine, Male, mitochondrial metabolism, Neurological disorder, Mitochondrion, 0302 clinical medicine, Spastic, Child, Genetics (clinical), Exome sequencing, ComputingMilieux_MISCELLANEOUS, Brain Diseases, genetics [Brain Diseases], Neurodegenerative Diseases, encephalopathy, Mitochondria, 3. Good health, Pedigree, developmental delay, Phenotype, Female, genetics [Mitochondrial Proteins], movement disorder, medicine.symptom, Adult, Adolescent, Hereditary spastic paraplegia, Encephalopathy, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Developmental Delay, Exome Sequencing, Hereditary Spastic Paraplegia, Hpdl, Leigh-like Syndrome, Mitochondrial Metabolism, Movement Disorder, Mitochondrial Proteins, Leigh-like syndrome, 03 medical and health sciences, Young Adult, Report, ddc:570, genetics [Spastic Paraplegia, Hereditary], Genetics, medicine, Humans, Spasticity, Amino Acid Sequence, hereditary spastic paraplegia, Allele, Alleles, Spastic Paraplegia, Hereditary, business.industry, HPDL, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, genetics [Neurodegenerative Diseases], Immunology, genetics [Mitochondria], business, exome sequencing, 030217 neurology & neurosurgery
Abstract

International audience; We report bi-allelic pathogenic HPDL variants as a cause of a progressive, pediatric-onset spastic movement disorder with variable clinical presentation. The single-exon gene HPDL encodes a protein of unknown function with sequence similarity to 4-hydroxyphenylpyruvate dioxygenase. Exome sequencing studies in 13 families revealed bi-allelic HPDL variants in each of the 17 individuals affected with this clinically heterogeneous autosomal-recessive neurological disorder. HPDL levels were significantly reduced in fibroblast cell lines derived from more severely affected individuals, indicating the identified HPDL variants resulted in the loss of HPDL protein. Clinical presentation ranged from severe, neonatal-onset neurodevelopmental delay with neuroimaging findings resembling mitochondrial encephalopathy to milder manifestation of adolescent-onset, isolated hereditary spastic paraplegia. All affected individuals developed spasticity predominantly of the lower limbs over the course of the disease. We demonstrated through bioinformatic and cellular studies that HPDL has a mitochondrial localization signal and consequently localizes to mitochondria suggesting a putative role in mitochondrial metabolism. Taken together, these genetic, bioinformatic, and functional studies demonstrate HPDL is a mitochondrial protein, the loss of which causes a clinically variable form of pediatric-onset spastic movement disorder.

Published
2020

17. De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene

Author

Giulia Barcia, Laurence Hubert, Emily Fassi, Julien Thevenon, Laurence Faivre, Philippe Lory, Daniel Medina-Cano, Pierre Blanc, Nathalie Boddaert, Nami Altin, Karine Siquier-Pernet, Marlène Rio, Céline Vidal, Jean Chemin, Sylvain Hanein, Holly H. Zimmerman, Marwan Shinawi, Patrick Nitschke, Vincent Cantagrel, Cécile Fourage, Nadia Bahi-Buisson, Christine Bole-Feysot, Jeanne Amiel, Ali Ahmad, Arnold Munnich, Michael Nicouleau, Stanislas Lyonnet, Laurence Colleaux, Isabelle Desguerre, Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-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), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), 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), 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], Plate Forme Paris Descartes de Bioinformatique (BIP-D), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de neurologie pédiatrique [CHU Necker], Neuroimagerie en psychiatrie (U1000), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Radiologie et imagerie médicale [CHU Necker], Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, ANR-16-CE12-0005,SCD-Mec,Mécanismes développementaux des anomalies structurelles cérébelleuses(2016), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-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)-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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), 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 Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, 0301 basic medicine, Microcephaly, [SDV]Life Sciences [q-bio], Developmental Disabilities, medicine.disease_cause, Deep cerebellar nuclei, Cohort Studies, Calcium Channels, T-Type, Purkinje Cells, Epilepsy, 0302 clinical medicine, Cerebellum, Child, Exome sequencing, Mutation, Brain, Phenotype, Pedigree, Child, Preschool, Gain of Function Mutation, CACNA1G, Female, Cerebellar atrophy, medicine.symptom, voltage-gated calcium channel, Adult, medicine.medical_specialty, Adolescent, Cerebellar Ataxia, Biology, 03 medical and health sciences, cerebellar atrophy, Cerebellar Diseases, Intellectual Disability, Internal medicine, medicine, Humans, [SDV.GEN]Life Sciences [q-bio]/Genetics, Cerebellar ataxia, medicine.disease, de novo mutation, 030104 developmental biology, Endocrinology, Calcium, Calcium Channels, Neurology (clinical), Atrophy, Cav3.1, 030217 neurology & neurosurgery
Abstract

IF 10.848; International audience; Cerebellar atrophy is a key neuroradiological finding usually associated with cerebellar ataxia and cognitive development defect in children. Unlike the adult forms, early onset cerebellar atrophies are classically described as mostly autosomal recessive conditions and the exact contribution of de novo mutations to this phenotype has not been assessed. In contrast, recent studies pinpoint the high prevalence of pathogenic de novo mutations in other developmental disorders such as intellectual disability, autism spectrum disorders and epilepsy. Here, we investigated a cohort of 47 patients with early onset cerebellar atrophy and/or hypoplasia using a custom gene panel as well as whole exome sequencing. De novo mutations were identified in 35% of patients while 27% had mutations inherited in an autosomal recessive manner. Understanding if these de novo events act through a loss or a gain of function effect is critical for treatment considerations. To gain a better insight into the disease mechanisms causing these cerebellar defects, we focused on CACNA1G, a gene not yet associated with the early-onset form. This gene encodes the Cav3.1 subunit of T-type calcium channels highly expressed in Purkinje neurons and deep cerebellar nuclei. We identified four patients with de novo CACNA1G mutations. They all display severe motor and cognitive impairment, cerebellar atrophy as well as variable features such as facial dysmorphisms, digital anomalies, microcephaly and epilepsy. Three subjects share a recurrent c.2881G>A/p.Ala961Thr variant while the fourth patient has the c.4591A>G/p.Met1531Val variant. Both mutations drastically impaired channel inactivation properties with significantly slower kinetics (∼5 times) and negatively shifted potential for half-inactivation (>10 mV). In addition, these two mutations increase neuronal firing in a cerebellar nuclear neuron model and promote a larger window current fully inhibited by TTA-P2, a selective T-type channel blocker. This study highlights the prevalence of de novo mutations in early-onset cerebellar atrophy and demonstrates that A961T and M1531V are gain of function mutations. Moreover, it reveals that aberrant activity of Cav3.1 channels can markedly alter brain development and suggests that this condition could be amenable to treatment.

Published
2018

18. The emerging roles of MicroRNAs in autism spectrum disorders

Author

Lam Son Nguyen, Julien Fregeac, Laurence Colleaux, 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), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Autism Spectrum Disorder, Cognitive Neuroscience, Biology, behavioral disciplines and activities, 03 medical and health sciences, Behavioral Neuroscience, mental disorders, Neuroplasticity, microRNA, medicine, Humans, Synapse formation, MESH: Neuronal Plasticity, Epigenetics, Brain function, MESH: Autism Spectrum Disorder, Neuronal Plasticity, MESH: Humans, Epigenetic, Autism spectrum disorders, medicine.disease, MicroRNAs, 030104 developmental biology, Neuropsychology and Physiological Psychology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, Synaptic plasticity, MESH: Biomarkers, Autism, MESH: MicroRNAs, Neuroscience, Biomarkers
Abstract

International audience; Autism spectrum disorders (ASD) are heritable neurodevelopmental conditions characterized by impairment in social interaction and communication and restricted, repetitive, stereotyped patterns of behavior. ASD likely involve deregulation of multiple genes related to brain function and development. MicroRNAs (miRNAs) are post-transcriptional regulators that play key roles in brain development, synapse formation and fine-tuning of genes underlying synaptic plasticity and memory formation. Here, we review recent studies providing genetic and molecular links between miRNA deregulation and ASD pathophysiology. These findings highlight the potential of miRNAs as both biomarkers and therapeutic tools in ASD.

Published
2016

20. Exome sequencing findings in 27 patients with myoclonic-atonic epilepsy: Is there a major genetic factor?

Author

Florine Verny, Giulia Barcia, Laurence Colleaux, Isabelle Desguerre, Rima Nabbout, Nicole Chemaly, Laura Routier, Epilepsies de l'Enfant et Plasticité Cérébrale (U1129), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Épilepsie de l'enfant et plasticité cérébrale (Inserm U663), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie pédiatrique [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), 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]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, Candidate gene, Epilepsies, Myoclonic, 030105 genetics & heredity, Biology, 03 medical and health sciences, Epilepsy, Intellectual disability, Exome Sequencing, Genetics, medicine, STXBP1, Humans, Genetic Predisposition to Disease, Age of Onset, Gene, Genetics (clinical), Exome sequencing, ComputingMilieux_MISCELLANEOUS, Alleles, Genetic Association Studies, Comparative Genomic Hybridization, Genetic heterogeneity, Infant, Electroencephalography, medicine.disease, 3. Good health, 030104 developmental biology, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, CHD2, Child, Preschool, Mutation, Female
Abstract

Myoclonic-atonic epilepsy (MAE) is thought to have a genetic etiology. Mutations in CHD2, SLC2A1 and SLC6A1 genes have been reported in few patients showing often intellectual disability prior to MAE onset. We aimed to explore putative causal genetic factors in MAE. We performed array-CGH and whole-exome sequencing in 27 patients. We considered non-synonymous variants, splice acceptor, donor site mutations, and coding insertions/deletions. A gene was causal when its mutations have been already linked to epilepsy or other brain diseases or when it has a putative function in neuronal excitability or brain development. We identified candidate disease-causing variants in 11 patients (41%). Single variants were found in some known epilepsy-associated genes (namely CHD2, KCNT1, KCNA2 and STXBP1) but not in others (SLC2A1 and SLC6A1). One new candidate gene SUN1 requires further validation. MAE shows underlying genetic heterogeneity with only few cases linked to mutations in genes reported in developmental and epileptic encephalopathies.

Published
2019

21. Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy

Author

Montserrat Ruiz, Gholamreza Shariati, Cristina Pujades, Eric W. Klee, Odile Boespflug-Tanguy, Joseph G. Gleeson, Reza Maroofian, Filippo Vairo, Nathalie Launay, Stéphane Fourcade, Javier Joya, Lauren Brady, Mark A. Tarnopolsky, Nara Sobreira, Marc C. Patterson, Agatha Schlüter, Julie S. Cohen, Laurence Colleaux, Elizabeth Wohler, Carles Cornet, Jingmin Wang, Margit Burmeister, Neda Mazaheri, Isabelle Desguerre, Kiely N. James, Diana Rodriguez, Maria Eugenia Yoldi, Imen Dorboz, Huifang Yan, Dorothée Ville, Hamid Galehdari, Damir Musaev, Mary J H Willis, Ali Fatemi, Gaetan Lesca, Davide Rubbini, Maha S. Zaki, Aurora Pujol, Brendan C. Lanpher, Devesh C. Pant, Karine Siquier-Pernet, Javier Terriente, Carlos Casasnovas, Sergio Aguilera-Albesa, Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), 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), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de la Matière Condensée de Bordeaux (ICMCB), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Service de Génétique [HCL Groupement Hospitalier Est], Groupement hospitalier Lyon-Est, Department of Human Genetics, Department of Psychiatry, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-Molecular and Behavioral Neuroscience Institute, McMaster University [Hamilton, Ontario], Medical Research Council, Molecular and Clinical Sciences Institute - St George’s [London, UK] (Genetics Research Centre), University of London [London], Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Neurogenetics, Howard Hughes Medical Institute, Department of Neurosciences, University of California [San Diego] (UC San Diego), University of California-University of California, Developmental Biology Group, Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra [Barcelona], Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurometabolic Diseases Laboratory [Barcelona, Spain], Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of California (UC)-University of California (UC), Universitat Pompeu Fabra [Barcelona] (UPF), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Fatty Acid Desaturases, 0301 basic medicine, medicine.medical_specialty, Ceramide, Animals, Genetically Modified, 03 medical and health sciences, chemistry.chemical_compound, Myelin, 0302 clinical medicine, Internal medicine, Malalties hereditàries, Animals, Humans, Neurociències, Medicine, Neurodegeneration, Zebrafish, ComputingMilieux_MISCELLANEOUS, Dystonia, Fingolimod Hydrochloride, business.industry, Multiple sclerosis, Neurosciences, Brain, General Medicine, Zebrafish Proteins, medicine.disease, Fingolimod, Sphingolipid, 3. Good health, Disease Models, Animal, Hereditary Central Nervous System Demyelinating Diseases, Oligodendroglia, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, Cerebellar atrophy, business, Genetic disorders, Locomotion, Research Article, medicine.drug, Neuroscience
Abstract

Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole-exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in 19 patients from 13 unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity, and profound failure to thrive. MRI showed hypomyelination, thinning of the corpus callosum, and progressive thalamic and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patients' fibroblasts and muscle. Further, we used a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of Cer synthase by fingolimod, 1 step prior to DEGS1 in the pathway, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in a zebrafish model. These proof-of-concept results pave the way to clinical translation. This study was supported by the ISCIII (FIS PI14/00581) (cofunded by the European Regional Development Fund); ‘La Marató de TV3’ Foundation 345/C/2014 (to AP, C. Casasnovas, and CP); the Hesperia Foundation and CIBER on Rare Diseases (CIBERER) (ACCI14-759) and the Secretariat for Universities and Research of the Ministry of Business and Knowledge of the Government of Catalonia (2017SGR1206) to AP; the Spanish Ministry of Economy and Competitiveness (MINECO-FEDER) (BFU2015-67400-P) to CP; the Spanish Institute for Health Carlos III (Miguel Servet program CPII16/00016) to SF; CIBERER to NL and MR; and a predoctoral fellowship awarded to DP from the Government of Catalonia through L′Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR; FI-DGR 2014). XJ acknowledges a Sara Borrell postdoctoral fellowship from Instituto de Salud Carlos III.

Published
2019

22. Paraparésie spastique, épilepsie, retard de développement : mutation homozygote du gène HPDL

Author

Imene Fatima Boyakaz, Lamia Ali Pacha, Dalila Moualek, Mohamed Islam Kediha, Abdelkrim Saadi, Laurence Colleaux, and Radia Bouderba

Subjects
Neurology, Neurology (clinical)
Abstract

Introduction Les paraparesies spastiques hereditaires (PSH) sont un groupe de maladies neurodegeneratives heterogenes avec comme caracteristique commune une spasticite progressive des membres inferieurs parfois associee a une deficience intellectuelle. Observation Nous rapportons l’observation d’une famille algerienne non apparentee, composee d’un garcon de 8 ans et une fille de 7 ans, nes a terme avec retard de croissance intra-uterin et hypotonie neonatale. L’evolution est caracterisee par un retard psychomoteur severe et la survenue de crises tonicocloniques generalisees des l’âge de 2 mois. L’examen retrouve une tetraparesie spastique, une scoliose, une dystonie axiale, des troubles de la motilite oculaire, une microcephalie (−5ds), une petite taille (−3, −4ds) et des signes dysmorphiques non specifiques. L’imagerie cerebrale montre chez les deux patients une reduction du volume de la substance blanche avec une predominance parieto-occipitale, un corps calleux tres mince, une augmentation diffuse du signal de la substance blanche periventriculaire et des fibres en U. L’electroencephalogramme montre un trace de fond lent, mal organise avec une activite epileptiforme focale et generalisee. Lactate LCR a 6,20 mmol/L (0,89–1,66 L) chez la fille. Le dosage des enzymes leucocytaires, l’electromyographie et l’examen ophtalmologique sont sans particularites. L’exome sequencing a permis l’identification d’une mutation homozygote du gene HPDL (c.342_343 insTGCC p. Ala115Cys fs*82). Discussion A ce jour, quinze patients supplementaires ont ete rapportes, porteurs de 10 mutations. Dix patients presentent avant l’âge d’un an, une spasticite progressive avec troubles visuels, microcephalie, crises epileptiques. 1/3 des patients presentent une paraparesie spastique pure a l’âge 14 ans. L’elevation des lactates, les modifications de l’activite des enzymes respiratoires suggerent un dysfonctionnement mitochondrial. Conclusion Les mutation HPDL sont a l’origine de 3 phenotypes ; encephalopathie congenitale, paraparesie spastique pure juvenile (PSH 83) et infantile intermediaire. Les etudes ulterieures sont necessaires pour definir le spectre phenotypique.

Published
2021

23. NONO Detects the Nuclear HIV Capsid to Promote cGAS-Mediated Innate Immune Activation

Author

Archa H. Fox, Aymeric Silvin, Lucie Etienne, Cécile Conrad, Baoyu Zhao, Matteo Gentili, Fenglei Du, Xavier Lahaye, Charles S. Bond, Lea Picard, Gavin J. Knott, Laurence Colleaux, Jeanne Amiel, Pingwei Li, Mabel Jouve, Elina Zueva, Mathieu Maurin, Nicolas Manel, Marlène Rio, Francesca Nadalin, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Biologie Computationnelle et Quantitative = Laboratory of Computational and Quantitative Biology (LCQB), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Northwest A and F University, 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), Université Paris Descartes - Paris 5 (UPD5), 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), CHU Necker - Enfants Malades [AP-HP], Molecular Endocrinology and Pharmacology, Harry Perkins Institute of Medical Research, The University of Western Australia (UWA), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), 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), Recherches Translationnelles sur le VIH et les maladies infectieuses (TransVIHMI), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche pour le Développement (IRD)-Université Montpellier 1 (UM1)-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Universtié Yaoundé 1 [Cameroun]-Université de Montpellier (UM)

Subjects
0301 basic medicine, viruses, Human immunodeficiency virus (HIV), HIV Infections, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, chemistry.chemical_compound, Capsid, Nuclear Matrix-Associated Proteins, medicine, Humans, Dna viral, ComputingMilieux_MISCELLANEOUS, Cell Nucleus, Innate immune system, ATP synthase, biology, Macrophages, Membrane Proteins, RNA-Binding Proteins, virus diseases, Dendritic Cells, biochemical phenomena, metabolism, and nutrition, Nucleotidyltransferases, Virology, Immunity, Innate, 3. Good health, DNA-Binding Proteins, 030104 developmental biology, medicine.anatomical_structure, chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, DNA, Viral, HIV-2, Host-Pathogen Interactions, HIV-1, biology.protein, Octamer Transcription Factors, Capsid Proteins, Nucleus, DNA, Signal Transduction, Immune activation
Abstract

Detection of viruses by innate immune sensors induces protective antiviral immunity. The viral DNA sensor cyclic GMP-AMP synthase (cGAS) is necessary for detection of HIV by human dendritic cells and macrophages. However, synthesis of HIV DNA during infection is not sufficient for immune activation. The capsid protein, which associates with viral DNA, has a pivotal role in enabling cGAS-mediated immune activation. We now find that NONO is an essential sensor of the HIV capsid in the nucleus. NONO protein directly binds capsid with higher affinity for weakly pathogenic HIV-2 than highly pathogenic HIV-1. Upon infection, NONO is essential for cGAS activation by HIV and cGAS association with HIV DNA in the nucleus. NONO recognizes a conserved region in HIV capsid with limited tolerance for escape mutations. Detection of nuclear viral capsid by NONO to promote DNA sensing by cGAS reveals an innate strategy to achieve distinction of viruses from self in the nucleus.

Published
2018

24. Author response: High N-glycan multiplicity is critical for neuronal adhesion and sensitizes the developing cerebellum to N-glycosylation defect

Author

Laurence Colleaux, Ida Chiara Guerrera, Catherine Faivre-Sarrailh, Jean-Charles Bizot, Michael Nicouleau, François Foulquier, Vincent Cantagrel, Joanna Lipecka, Ekin Ucuncu, Daniel Medina-Cano, Nathalie Lefort, Lam Son Nguyen, and Christian Thiel

Subjects
Glycan, N-linked glycosylation, biology, Chemistry, biology.protein, Developing cerebellum, Multiplicity (chemistry), Cell biology
Published
2018

25. 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

26. 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

27. Xq25 duplication: the crucial role of the STAG2 gene in this novel human cohesinopathy

Author

S. Romana, Michel Vekemans, Anne Philippe, Sylvie Nusbaum, Catherine Turleau, Valérie Malan, Julie Steffann, D. Lamblin, Bérénice Doray, Marie-Line Jacquemont, Catherine Patrat, Valérie Cormier-Daire, Camille Leroy, and Laurence Colleaux

Subjects
0301 basic medicine, Genetics, Cohesin complex, Biology, medicine.disease, Phenotype, X-inactivation, 03 medical and health sciences, 030104 developmental biology, Gene duplication, Intellectual disability, medicine, Copy-number variation, Gene, Genetics (clinical), Comparative genomic hybridization
Abstract

The Xq25 duplications syndrome has recently emerged as a distinct clinical entity. We report here on six new patients belonging to two unrelated families and harbouring an Xq25 microduplication detected by array CGH. Similarly to previously reported cases, the phenotype of our patients is characterized by delayed milestones, speech disturbance, intellectual disability, abnormal behaviours and a characteristic facial dysmorphism. The common duplicated interval allowed further refinement of the shortest region of overlap to 173 kb, including only one gene, STAG2, which encodes a component of the cohesin complex. We suggest that increased STAG2 gene copy number and dysregulation of its downstream target genes may be responsible for the specific clinical findings of this syndrome. Therefore, the Xq25 microduplication could be considered as a novel cohesinopathy, thus increasing the group of these disorders.

Published
2015

28. Distal duplication of chromosome 16q22.1q23.1 in a Vietnamese patient with midface hypoplasia and intellectual disability

Author

Kiem Lien Thi Nguyen, Laurence Colleaux, Lam Son Nguyen, Van Hai Nong, Thu Hien Nguyen, Diem Ngoc Ngo, Pierre Landrieu, Van Anh Pham, Valérie Malan, Huy Hoang Nguyen, Giulia Barcia, Hanoi School of Public Health (HUPH), Molecular and pathophysiological bases of cognitive disorders (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 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), 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)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Male, Pediatrics, medicine.medical_specialty, Adolescent, Vietnamese, Visual impairment, Forked tongue, Craniofacial Abnormalities, 03 medical and health sciences, Ptosis, Intellectual Disability, Gene duplication, Intellectual disability, Chromosome Duplication, Genetics, medicine, Humans, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetic Association Studies, Comparative Genomic Hybridization, business.industry, Facies, medicine.disease, language.human_language, 030104 developmental biology, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Vietnam, Chromosomes, Human, Pair 1, language, medicine.symptom, Presentation (obstetrics), business, Chromosomes, Human, Pair 16, Comparative genomic hybridization
Abstract

The clinical presentation of distal duplications of the long arm of chromosome (chr) 16 is currently not well described. Only one case of microduplication of chr16q22.1 and another involving the chr16q22.1q23.1 region have been reported so far. Here, using array comparative genomic hybridization, we identified a second case of chr16q22.1q23.1 duplication in a Vietnamese boy, who shares significant clinical phenotype with the previously described case. Aside from developmental delay, intellectual disability and midface hypoplasia, our patient also displays a forked tongue, visual impairment and external ptosis. Our report further expands the clinical spectrum associated with duplication of this region.

Published
2017

30. Extracellular proteases and their inhibitors ingenetic diseases of the central nervous system

Author

Florence Molinari, Peter Sonderegger, Virginia Meskanaite, Laurence Colleaux, Arnold Munnich, Aix Marseille Université (AMU), 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), and Handicaps génétiques de l'enfant (Inserm U393)

Subjects
Proteases, MESH: Genetic Diseases, Inborn, Serine Proteinase Inhibitors, MESH: Mutation, MESH: Serine Proteinase Inhibitors, Serpin, MESH: Neuropeptides, C1-inhibitor, 03 medical and health sciences, 0302 clinical medicine, Central Nervous System Diseases, MESH: Serpins, Genetics, medicine, Humans, Protease inhibitor (pharmacology), MESH: Serine Endopeptidases, Molecular Biology, Serpins, Genetics (clinical), 030304 developmental biology, Factor IX, Serine protease, 0303 health sciences, MESH: Humans, biology, Neuropeptides, Serine Endopeptidases, Genetic Diseases, Inborn, Proteolytic enzymes, Genetic disorder, General Medicine, medicine.disease, MESH: Central Nervous System Diseases, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Immunology, biology.protein, 030217 neurology & neurosurgery, medicine.drug
Abstract

International audience; Cumulative evidence has shown that a delicate balance between serine proteases and their inhibitors is crucial for normal functioning of several biological pathways. The importance of proteases and their inhibitors is well documented in several human diseases. Among them, the best documented are hemophilia B, a genetic deficiency of the serine protease coagulation factor IX and serpinophathies. Alpha-1-antitrypsin deficiency (MIM 107400), is associated with early-onset emphysema and liver disease, while hereditary angioedema (HANE; MIM 106100) is caused by mutations in the C1 inhibitor, a serpin involved in the regulation of the complement cascade. Recently, two human genetic diseases of the central nervous system have been related to mutations in components of extracellular proteolytic systems. Here, we review the recent advances in this field.

Published
2017

31. 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

32. Phenotype-genotype correlations in 17 new patients with an Xp11.23p11.22 microduplication and review of the literature

Author

Fabienne Giuliano, Olivier Pichon, Lucile Pinson, Bénédicte Duban-Bedu, Valérie Malan, Emilie Bourel-Ponchel, Rima Nabbout, Mathilde Nizon, Delphine Héron, Marlène Rio, Béatrice Bourgois, Odile Boute, Alice Goldenberg, Sarah Grotto, Sylvie Nusbaum, Odile Raoul, Catherine Turleau, Eric Le Galloudec, Joris Andrieux, Houda Karmous-Benailly, Bruno Delobel, Marie-Christine de Blois, Boris Keren, Martine Le Merrer, Laurence Colleaux, Cédric Le Caignec, Albert David, Serge Romana, Jean-Michel Lapierre, Agnès Roubertie, Didier Lacombe, Caroline Rooryck, Michel Vekemans, Michèle Mathieu-Dramard, and Anne-Gaëlle Le Moing

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Candidate gene, Adolescent, Chromosomal rearrangement, Epilepsy, Segmental Duplications, Genomic, Intellectual disability, Genetics, medicine, Humans, Child, Genetic Association Studies, Genetics (clinical), Segmental duplication, Chromosomes, Human, X, Comparative Genomic Hybridization, business.industry, Chromosome Mapping, Electroencephalography, West Syndrome, medicine.disease, Phenotype, Child, Preschool, Cohort, Female, business, Comparative genomic hybridization
Abstract

Array comparative genomic hybridization (array CGH) has proven its utility in uncovering cryptic rearrangements in patients with X-linked intellectual disability. In 2009, Giorda et al. identified inherited and de novo recurrent Xp11.23p11.22 microduplications in two males and six females from a wide cohort of patients presenting with syndromic intellectual disability. To date, 14 females and 5 males with an overlapping microduplication have been reported in the literature. To further characterize this emerging syndrome, we collected clinical and microarray data from 17 new patients, 10 females, and 7 males. The Xp11.23p11.2 microduplications detected by array CGH ranged in size from 331 Kb to 8.9 Mb. Five patients harbored 4.5 Mb recurrent duplications mediated by non-allelic homologous recombination between segmental duplications and 12 harbored atypical duplications. The chromosomal rearrangement occurred de novo in eight patients and was inherited in six affected males from three families. Patients shared several common major characteristics including moderate to severe intellectual disability, early onset of puberty, language impairment, and age related epileptic syndromes such as West syndrome and focal epilepsy with activation during sleep evolving in some patients to continuous spikes-and-waves during slow sleep. Atypical microduplications allowed us to identify minimal critical regions that might be responsible for specific clinical findings of the syndrome and to suggest possible candidate genes: FTSJ1 and SHROOM4 for intellectual disability along with PQBP1 and SLC35A2 for epilepsy. Xp11.23p11.22 microduplication is a recently-recognized syndrome associated with intellectual disability, epilepsy, and early onset of puberty in females. In this study, we propose several genes that could contribute to the phenotype.

Published
2014

33. Multiple congenital anomalies-intellectual disability (MCA-ID) and neuroblastoma in a patient harboring a de novo 14q23.1q23.3 deletion

Author

Laurence Colleaux, Damien Sanlaville, Louise Galmiche, Serge Romana, Emmanuel Plouvier, Thierry Leblanc, Anne Guimier, Jeanne Amiel, Isabelle Radford, Stanislas Lyonnet, Loïc de Pontual, and Daphné Lehalle

Subjects
Male, medicine.medical_specialty, Spherocytosis, Loss of heterozygosity, Pheochromocytoma, Neuroblastoma, Paraganglioma, Intellectual Disability, Internal medicine, Genetics, medicine, Genetic predisposition, Humans, Abnormalities, Multiple, In Situ Hybridization, Fluorescence, Genetics (clinical), Chromosomes, Human, Pair 14, Comparative Genomic Hybridization, business.industry, Facies, Infant, medicine.disease, Hypoplasia, Endocrinology, Karyotyping, Cancer research, Chromosome Deletion, Haploinsufficiency, business
Abstract

Neuroblastoma is the most frequent extra cranial solid tumor in infants and children. Genetic predisposition to neuroblastoma has been suspected previously due to familial cases of sporadic NB and predisposition to NB in several syndromes. Here, we report on a de novo 14q23.1-q23.3 microdeletion in a male presenting with a neuroblastoma diagnosed at 9 months, and spherocytosis, congenital heart defect, cryptorchidism, hypoplasia of corpus callosum, epilepsy, and developmental delay. Myc-associated-factor X (MAX) haploinsufficiency could be regarded as the predisposing factor to NB. Indeed 14q deletion is a recurrent somatic rearrangement in NB and MAX somatic and germline loss of function mutation have recently been described in pheochromocytoma and paraganglioma. However, MAX was expressed in the tumor of the patient we report on and, accordingly, loss of heterozygosity, mutation, or promoter methylation were excluded. In addition, we discuss the potential involvement in the clinical spectrum presented by the patient of five of the deleted genes, namely DAAM1, PLEKHG3, SPTB, AKAP5, and ARID4A.

Published
2014

34. Profiling olfactory stem cells from living patients identifies miRNAs relevant for autism pathophysiology

Author

Karine Siquier-Pernet, Claire Rougeulle, Marylin Lepleux, Francois Feron, Bruno Gepner, Julien Fregeac, Yann Humeau, Laurence Colleaux, Anne Philippe, Lam Son Nguyen, Christelle Martin, Melanie Makhlouf, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interdisciplinary Institute for Neuroscience (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), ANDRA, Agence Nationale pour la Gestion des Déchets Radioactifs (ANDRA), LIttoral ENvironnement et Sociétés - UMR 7266 (LIENSs), Université de La Rochelle (ULR)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Parole et Langage (LPL), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Interdisciplinary Institute for Neuroscience, ANR-10-IBHU-0001/10-IBHU-0001,MMO (IHU-CANCER),MMO (IHU-CANCER)(2010), ANR-12-SAMA-0001,SAMENTA 2012 : EPI - ASD,Santé Mentales et Addictions (SAMENTA) Edition 2012 : 'Contributions des anomalies épigénomiques à l’étiologie des troubles autistiques', Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Laboratory of Molecular and pathophysiological bases of cognitive disorders, Sorbonne Université (SU), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-10-IBHU-0001,MMO (IHU-CANCER),Institut de Médecine Personnalisée du Cancer(2010), ANR-12-SAMA-0001,EPI-ASD,Contributions des anomalies épigénomiques à l'étiologie des troubles autistiques(2012), BMC, BMC, Instituts Hospitalo-Universitaires B - Institut de Médecine Personnalisée du Cancer - - MMO (IHU-CANCER)2010 - ANR-10-IBHU-0001 - IBHU - VALID, Santé Mentale et Addictions - Contributions des anomalies épigénomiques à l'étiologie des troubles autistiques - - EPI-ASD2012 - ANR-12-SAMA-0001 - SAMENTA - VALID, Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Interdisciplinaire de Neurosciences ( IINS ), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique ( CNRS ), Centre épigénétique et destin cellulaire ( EDC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN ( NICN ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), ANR-10-IBHU-0001/10-IBHU-0001,MMO (IHU-CANCER),MMO (IHU-CANCER) ( 2010 ), and Centre épigénétique et destin cellulaire (EDC)

Subjects
Male, 0301 basic medicine, Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], Hippocampus, Transcriptome, Mice, 0302 clinical medicine, Neurodevelopmental disorder, 3' Untranslated Regions, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Neurons, MicroRNA, Autism spectrum disorders, Neural stem cell, [SDV] Life Sciences [q-bio], Adult Stem Cells, Psychiatry and Mental health, medicine.anatomical_structure, Organ Specificity, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Stem cell, Astrocyte, Adult stem cell, Adult, Genetic Vectors, Biology, Real-Time Polymerase Chain Reaction, Young Adult, 03 medical and health sciences, Olfactory Mucosa, Developmental Neuroscience, microRNA, medicine, Animals, Humans, Molecular Biology, [ SDV ] Life Sciences [q-bio], Olfactory mucosa stem cells, Research, Lentivirus, Fibroblasts, Neuron, medicine.disease, Human genetics, MicroRNAs, 030104 developmental biology, Astrocytes, Neuroscience, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Background Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders caused by the interaction between genetic vulnerability and environmental factors. MicroRNAs (miRNAs) are key posttranscriptional regulators involved in multiple aspects of brain development and function. Previous studies have investigated miRNAs expression in ASD using non-neural cells like lymphoblastoid cell lines (LCL) or postmortem tissues. However, the relevance of LCLs is questionable in the context of a neurodevelopmental disorder, and the impact of the cause of death and/or post-death handling of tissue likely contributes to the variations observed between studies on brain samples. Methods miRNA profiling using TLDA high-throughput real-time qPCR was performed on miRNAs extracted from olfactory mucosal stem cells (OMSCs) biopsied from eight patients and six controls. This tissue is considered as a closer tissue to neural stem cells that could be sampled in living patients and was never investigated for such a purpose before. Real-time PCR was used to validate a set of differentially expressed miRNAs, and bioinformatics analysis determined common pathways and gene targets. Luciferase assays and real-time PCR analysis were used to evaluate the effect of miRNAs misregulation on the expression and translation of several autism-related transcripts. Viral vector-mediated expression was used to evaluate the impact of miRNAs deregulation on neuronal or glial cells functions. Results We identified a signature of four miRNAs (miR-146a, miR-221, miR-654-5p, and miR-656) commonly deregulated in ASD. This signature is conserved in primary skin fibroblasts and may allow discriminating between ASD and intellectual disability samples. Putative target genes of the differentially expressed miRNAs were enriched for pathways previously associated to ASD, and altered levels of neuronal transcripts targeted by miR-146a, miR-221, and miR-656 were observed in patients’ cells. In the mouse brain, miR-146a, and miR-221 display strong neuronal expression in regions important for high cognitive functions, and we demonstrated that reproducing abnormal miR-146a expression in mouse primary cell cultures leads to impaired neuronal dendritic arborization and increased astrocyte glutamate uptake capacities. Conclusions While independent replication experiments are needed to clarify whether these four miRNAS could serve as early biomarkers of ASD, these findings may have important diagnostic implications. They also provide mechanistic connection between miRNA dysregulation and ASD pathophysiology and may open up new opportunities for therapeutic. Electronic supplementary material The online version of this article (doi:10.1186/s13229-015-0064-6) contains supplementary material, which is available to authorized users.

Published
2016

35. Les mutations du gène NONO sont responsables d’un nouveau syndrome de déficience intellectuelle lié au dysfonctionnement des synapses inhibitrices

Author

Steven A. Brown, Laurence Colleaux, Marlène Rio, Dennis Mircsof, Maéva Langouët, Jeanne Amiel, 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 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), 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), University of Zurich, 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 Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP]

Subjects
0301 basic medicine, 10050 Institute of Pharmacology and Toxicology, 610 Medicine & health, General Medicine, Biology, Molecular biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 1300 General Biochemistry, Genetics and Molecular Biology, 570 Life sciences, biology, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2016

36. Déficiences intellectuelles

Author

Wil Buntinx, Christine Cans, LAURENCE COLLEAUX, Yannick Courbois, Martin Debbané, Vincent Desportes, Jean-Jacques Detraux, Bruno Facon, Marie-Claire Haelewyck, Delphine Heron, Geneviève Petitpierre, Eric Plaisance, Université de Lille, CHU Grenoble, Imagine - Institut des maladies génétiques [IMAGINE - U1163], 109539|||Psychologie : Interactions, Temps, Emotions, Cognition (PSITEC) - ULR 4072 [PSITEC], Institut des Sciences cognitives Marc Jeannerod - Laboratoire sur le langage, le cerveau et la cognition [L2C2], 415060|||Sciences Cognitives et Sciences Affectives (SCALab) - UMR 9193 [SCALab], Université de Mons [UMons], Université de Fribourg = University of Fribourg [UNIFR], Centre de recherche sur les liens sociaux [CERLIS - UMR 8070], Dupuis, Christine, Governor Kremers Center pour personnes déficientes intellectuelles [Maastricht, Pays-Bas], Université de Maastricht, Registre des Handicaps de l'Enfant et Observatoire Perinatal de l'Isère et des deux Savoie (RHEOP), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Conseils Généraux de l'Isère, de la savoie et de la Haute-Savoie, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Psychologie : Interactions, Temps, Emotions, Cognition (PSITEC) - ULR 4072 (PSITEC), Unité de Psychologie clinique développementale [Genève, Suisse], Faculté de Psychologie et de Sciences de l’Éducation [Genève, Suisse], Université de Genève = University of Geneva (UNIGE)-Université de Genève = University of Geneva (UNIGE), Institut des Sciences cognitives Marc Jeannerod - Laboratoire sur le langage, le cerveau et la cognition (L2C2), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Département de Psychologie : Cognition et Comportement [Bruxelles, Belgique] (Psychopédagogie), Université de Liège-Université libre de Bruxelles (ULB), Laboratoire Sciences Cognitives et Sciences Affectives - UMR 9193 (SCALab), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Service d'Orthopédagogie Clinique - FPSE, Université de Mons (UMons), Unité Fonctionnelle de Génétique Clinique [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), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Département de Pédagogie Spécialisée [Fribourg, Suisse], University of Fribourg, Centre de recherche sur les liens sociaux (CERLIS - UMR 8070), Université Sorbonne Nouvelle - Paris 3-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Institut national de la santé et de la recherche médicale(INSERM), Université de Genève (UNIGE)-Université de Genève (UNIGE), École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Sciences Cognitives et Sciences Affectives (SCALab) - UMR 9193 (SCALab), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université de Fribourg, École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université de Fribourg = University of Fribourg (UNIFR)

Subjects
Santé mentale, Quotient intellectuel, Comportement adaptatif, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Dépistage néonatal, Environnement social, Autonomie personnelle, Diagnostic, Personnes handicapées, Collection Expertise collective / ISBN 978-2-7598-1865-5, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

La « déficience intellectuelle » est définie par un déficit de l’intelligence et des limitations du fonctionnement adaptatif apparaissant avant l’âge adulte. La situation de handicap qui peut en résulter ne dépend pas seulement de la présence de la déficience intellectuelle, mais également de facteurs environnementaux ne favorisant pas la pleine participation de la personne à la communauté et son insertion totale dans la société.La déficience intellectuelle est fréquente puisqu’ environ 1 à 2 % de la population sont concernés.L’explosion récente des connaissances, tant sur les causes des déficiences intellectuelles que sur les processus cognitifs et adaptatifs sous-jacents, permet de mieux appréhender le fonctionnement des personnes avec déficience intellectuelle ; de nouvelles stratégies d’apprentissages, d’accompagnement et de soutien, mieux adaptées, sont proposées. Toutefois, ces connaissances restent insuffisamment partagées et mises au service des personnes.Sollicitée par la Caisse Nationale de Solidarité pour l’Autonomie (CNSA), cette expertise collective fait le bilan des connaissances actuelles dans trois champs : Définitions, repérage et diagnostic ; Apprentissages, développement et compétences des personnes avec une déficience intellectuelle ; Accompagnement tout au long de la vie. Le groupe d’experts propose également de nombreuses recommandations d’actions et de recherche.

Published
2016

37. Refining the phenotype associated with CASC5 mutation

Author

Marc Abramowicz, Karine Siquier-Pernet, Patrick Nitschke, Christine Bole-Feysot, Myriam Abada-Dendib, Florine Verny, Malika Chaouch, Abdelkrim Saadi, Arnold Munnich, Laurence Colleaux, Imagine - Institut des maladies génétiques (IMAGINE - U1163), 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), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), 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, CHU Ben Aknoun - Centre Hospitalo Universitaire de Ben Aknoun [Alger], Department of Medical Genetics [Bruxelles], Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), 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)-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 Hôpital Erasme (Bruxelles)

Subjects
0301 basic medicine, Adult, Male, Microcephaly, DNA Mutational Analysis, Consanguinity, Biology, Short stature, Polymorphism, Single Nucleotide, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, Neurodevelopmental disorder, Intellectual Disability, Genetics, medicine, Missense mutation, Humans, Family, Genetics (clinical), Exome sequencing, ComputingMilieux_MISCELLANEOUS, medicine.disease, Founder Effect, 3. Good health, Pedigree, 030104 developmental biology, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Codon, Nonsense, Algeria, Mutation (genetic algorithm), Female, medicine.symptom, Microtubule-Associated Proteins, Founder effect
Abstract

Autosomal recessive primary microcephaly is a neurodevelopmental disorder characterized by congenitally reduced head circumference by at least two standard deviations (SD) below the mean for age and gender. It is associated with nonprogressive mental retardation of variable degree, minimal neurological deficit with no evidence of architectural anomalies of the brain. So far, 12 genetic loci (MCPH1-12) and corresponding genes have been identified. Most of these encode centrosomal proteins. CASC5 is one the most recently unravelled genes responsible for MCPH with mutations reported in three consanguineous families of Moroccan origin, all of whom harboured the same CASC5 homozygous mutation (c.6125G>A; p.Met2041Ile). Here, we report the identification, by whole exome sequencing, of the same missense mutation in a consanguineous Algerian family. All patients exhibited a similar clinical phenotype, including congenital microcephaly with head circumferences ranging from -3 to -4 standard deviations (SD) after age 5 years, moderate to severe cognitive impairment, short stature (adult height -3 SD), dysmorphic features included a sloping forehead, thick eyebrows, synophris and a low columella. Severe vermis hypoplasia and a large cyst of the posterior fossa were observed in one patient. Close microsatellite markers showed identical alleles in the Algerian the previously and Moroccan patients. This study confirms the involvement of CASC5 in autosomal recessive microcephaly and supports the hypothesis of a founder effect of the c.6125G>A mutation. In addition, this report refines the phenotype of this newly recognized form of primary microcephaly.

Published
2016

38. NF-κB signalling requirement for brain myelin formation is shown by genotype/MRI phenotype correlations in patients with Xq28 duplications

Author

Arnold Munnich, Jeanne Amiel, Vassili Valayannopoulos, Jean-Paul Bonnefont, Marlène Rio, Roseline Gesny, Nadia Bahi-Buisson, Guy Froyen, Orianne Philippe, Laurence Colleaux, Nathalie Boddaert, Valérie Malan, Hilde Van Esch, and Geneviève Baujat

Subjects
Genetics, Central nervous system, Schwann cell, Biology, Phenotype, MECP2, Cell biology, White matter, medicine.anatomical_structure, IKBKG, Gene duplication, medicine, Axon, Genetics (clinical)
Abstract

One of the key signals regulating peripheral myelin formation by Schwann cell is the activation of the transcription factor NF-κB. Yet, whether NF-κB exerts similar functions in central myelin formation by oligodendrocytes remains largely unknown. We previously reported white matter abnormalities with unusual discordance between T2 and FLAIR sequences in a patient with intellectual disability and defective NF-κB signalling. These observations prompted us to hypothesise that NF-κB signalling may have a role in the axon myelination process of central neurons. We report here on five male patients with Xq28 duplications encompassing MECP2, three of which presented white matter anomalies on brain MRI. Array-CGH and FISH analyses demonstrated that brain abnormalities correlate with additional copies of the IKBKG, a gene encoding a key regulator of NF-κB activation. Quantitative RT-PCR experiments and κB-responsive reporter gene assays provide evidence that IKBKG overexpression causes impaired NF-κB signalling in skin fibroblasts derived from patients with white matter anomalies. These data further support the role of NF-κB signalling in astroglial cells for normal myelin formation of the central nervous system.

Published
2012

39. Mutations in NONO lead to syndromic intellectual disability and inhibitory synaptic defects

Author

Giovanna Bosshard, Steven J Moss, Christine Bole-Feysot, Jean-Marc Fritschy, Karine Siquier-Pernet, Patrick Nitschké, Olivier Alibeu, Ann-Kristina Fritz, Dennis Mircsof, David P. Wolfer, Florence Crestani, Markus Rudin, Steven A. Brown, Nathalie Boddaert, Rochelle M. Hines, Arnold Munnich, Jeanne Amiel, Petra Seebeck, Matej Žnidarič, Christina Koester, Nicolas Cagnard, Ludmila Gaspar, Maéva Langouët, Shiva K. Tyagarajan, Laurence Colleaux, Aileen Schröter, Marlène Rio, Sébastien Moutton, Katrina Prescott, 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), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], 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), Plateforme Bioinformatique [SFR Necker] (BIP-D), Institute of Anatomy, Universität Zürich [Zürich] = University of Zurich (UZH), Service de radiologie pédiatrique [CHU Necker], Department of Clnical Genetics, Chapel Allerton Hospital, Institute of Pharmacology and Toxicology [Zurich], University of Zurich, Brown, Steven A, 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), University of Zürich [Zürich] (UZH), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)

Subjects
Male, Protein family, Adolescent, 10050 Institute of Pharmacology and Toxicology, RNA-binding protein, 610 Medicine & health, Mice, Transgenic, Biology, Inhibitory postsynaptic potential, Article, Mice, Nuclear Matrix-Associated Proteins, Cellular neuroscience, Intellectual Disability, Intellectual disability, medicine, Transcriptional regulation, Animals, Humans, 10237 Institute of Biomedical Engineering, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Genetics, Gephyrin, General Neuroscience, 2800 General Neuroscience, Brain, RNA-Binding Proteins, Neural Inhibition, medicine.disease, Pedigree, DNA-Binding Proteins, Mice, Inbred C57BL, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Synapses, biology.protein, GABAergic, 570 Life sciences, biology, Octamer Transcription Factors, Neuroscience
Abstract

The NONO protein has been characterized as an important transcriptional regulator in diverse cellular contexts. Here we show that loss of NONO function is a likely cause of human intellectual disability and that NONO-deficient mice have cognitive and affective deficits. Correspondingly, we find specific defects at inhibitory synapses, where NONO regulates synaptic transcription and gephyrin scaffold structure. Our data identify NONO as a possible neurodevelopmental disease gene and highlight the key role of the DBHS protein family in functional organization of GABAergic synapses.

Published
2015

40. Utility of whole exome sequencing for the early diagnosis of pediatric-onset cerebellar atrophy associated with developmental delay in an inbred population

Author

Michael Nicouleau, Giulia Barcia, Mélanie Parisot, Arnold Munnich, Laurence Colleaux, Christine Bole-Feysot, Vincent Cantagrel, Isabelle Desguerre, Patrick Nitschke, Nathalie Boddaert, Nadia Bahi-Buisson, Cécile Masson, Daniel Medina-Cano, Marlène Rio, Hisham Megahed, Karine Siquier-Pernet, Clinical Genetics Department [Dokki, Egypt], Human Genetics and Genome Research Division [Dokki, Egypt]-National Research Center [Dokki, Egypt], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Service de neurologie 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 de Génétique Médicale [CHU Necker], Service de radiologie pédiatrique [CHU Necker], ANR-12-PDOC-0026,CerID-Gene,Mécanismes génétiques et physiopathologiques responsables de déficiences intellectuelles associées à une malformation cérébelleuse(2012), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), Université Sorbonne Paris Cité (USPC), Epilepsies de l'Enfant et Plasticité Cérébrale (U1129), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroimagerie en psychiatrie (U1000), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), Structure Fédérative de Recherche Necker ( SFR Necker - UMS 3633 / US24 ), Assistance publique - Hôpitaux de Paris (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)-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 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], ANR-12-PDOC-0026,CerID-Gene,Mécanismes génétiques et physiopathologiques responsables de déficiences intellectuelles associées à une malformation cérébelleuse ( 2012 ), ANR-10-IAHU-0001/10-IAHU-0001,Imagine,Imagine ( 2010 ), BMC, BMC, Retour Post-Doctorant - Mécanismes génétiques et physiopathologiques responsables de déficiences intellectuelles associées à une malformation cérébelleuse - - CerID-Gene2012 - ANR-12-PDOC-0026 - PDOC - VALID, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, 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), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)

Subjects
Male, 0301 basic medicine, Proband, Exome sequencing, Developmental Disabilities, [SDV]Life Sciences [q-bio], Intellectual disability, 0302 clinical medicine, Exome, Genetics(clinical), Pharmacology (medical), Molybdenum cofactor deficiency, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, KIF1A, Genetics, Medicine(all), MOCS2, Brain, General Medicine, Magnetic Resonance Imaging, 3. Good health, [SDV] Life Sciences [q-bio], Phenotype, Child, Preschool, Cerebellum atrophy, Female, Cerebellar atrophy, medicine.symptom, Cerebellar Ataxia, Biology, 03 medical and health sciences, Atrophy, medicine, Humans, Cerebellar ataxia, [ SDV ] Life Sciences [q-bio], Research, Sequence Analysis, DNA, medicine.disease, Human genetics, Early Diagnosis, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, 030217 neurology & neurosurgery
Abstract

Background Cerebellar atrophy and developmental delay are commonly associated features in large numbers of genetic diseases that frequently also include epilepsy. These defects are highly heterogeneous on both the genetic and clinical levels. Patients with these signs also typically present with non-specific neuroimaging results that can help prioritize further investigation but don’t suggest a specific molecular diagnosis. Methods To genetically explore a cohort of 18 Egyptian families with undiagnosed cerebellar atrophy identified on MRI, we sequenced probands and some non-affected family members via high-coverage whole exome sequencing (WES; >97 % of the exome covered at least by 30x). Patients were mostly from consanguineous families, either sporadic or multiplex. We analyzed WES data and filtered variants according to dominant and recessive inheritance models. Results We successfully identified disease-causing mutations in half of the families screened (9/18). These mutations are located in seven different genes, PLA2G6 being the gene most frequently mutated (n = 3). We also identified a recurrent de novo mutation in the KIF1A gene and a molybdenum cofactor deficiency caused by the loss of the start codon in the MOCS2A open-reading frame in a mildly affected subject. Conclusions This study illustrates the necessity of screening for dominant mutations in WES data from consanguineous families. Our identification of a patient with a mild and improving phenotype carrying a previously characterized severe loss of function mutation also broadens the clinical spectrum associated with molybdenum cofactor deficiency. Electronic supplementary material The online version of this article (doi:10.1186/s13023-016-0436-9) contains supplementary material, which is available to authorized users.

Published
2015

41. A novel mutation in STXBP1 causing epileptic encephalopathy (late onset infantile spasms) with partial respiratory chain complex IV deficiency

Author

Rima Nabbout, Agnès Rötig, Karine Siquier-Pernet, Marlène Rio, Giulia Barcia, Christine Barnerias, Laurence Colleaux, Isabelle Desguerre, and Arnold Munnich

Subjects
Male, Mitochondrial DNA, Pediatrics, medicine.medical_specialty, Ohtahara syndrome, Mitochondrial disease, Nonsense mutation, Late onset, Syntaxin binding, Electron Transport Complex IV, Epilepsy, Munc18 Proteins, Intellectual Disability, Genetics, medicine, Humans, STXBP1, Genetics (clinical), Lennox Gastaut Syndrome, business.industry, Infant, General Medicine, medicine.disease, Brain Waves, Codon, Nonsense, business, Spasms, Infantile
Abstract

STXBP1 (MUNC18.1), encoding syntaxin binding protein 1, has been reported in Ohtahara syndrome, a rare epileptic encephalopathy with suppression burst pattern on EEG, in patients with infantile spasms and in a few patients with nonsyndromic mental retardation without epilepsy. We report a patient who presented late onset infantile spasms. Epilepsy was controlled but the patient developed severe mental delay. A first diagnosis of mitochondrial disease was based on clinical presentation and on a partial deficit of respiratory chain complex IV, but molecular screening for mitochondrial genes was negative. The sequencing of STXBP1 gene found a de novo nonsense mutation (c.585C>G/p.Tyr195X). This observation widens the clinical spectrum linked to STXBP1 mutations with the description of a patient with late onset infantile spasms. It raises the question of the value of epilepsy genes screening in patients with uncertain, partial or unconfirmed mitochondrial dysfunction.

Published
2013

42. Rôle de miR-146a dans la différenciation et l’acquisition de l’identité neurale des cellules souches humaines : pertinence pour les troubles du spectre autistique

Author

Julien Fregeac, Christine Bole-Feysot, Lam Son Nguyen, Patrick Nitschké, Laurence Colleaux, and Oliver Pelle

Subjects
Anatomy
Abstract

Les troubles du spectre autistique sont un groupe de troubles neurodeveloppementaux causes par l’interaction entre des facteurs genetiques, epigenetiques et environnementaux. Parmi les facteurs epigenetiques, les microARNs (miARN) jouent un role cle dans le developpement neural et la formation des synapses. Nous et d’autres equipes avons recemment identifie la sur-expression du miARN miR-146a comme un marqueur commun a differents types de cellules issus des patients autistes : des cellules souches des muqueuses olfactives, des fibroblastes primaires et des lignees cellulaires lymphoblastoides. Ici, nous montrons par RT-qPCR que miR-146a est egalement sur-exprime dans le lobe temporal des enfants autistes (4–10 ans) mais pas chez les adolescents ni les adultes. Pour comprendre son role dans le developpement precoce, nous avons genere des lignees de cellules souches neurales humaines H9 sur-exprimant de facon stable miR-146a. Nous demontrons qu’a l’etat indifferencie la sur-expression du miR-146a n’a aucun effet sur la proliferation et le taux d’apoptose de ces cellules. En revanche, dans des conditions de differentiation, miR-146a accelere significativement la croissance et le branchement des neurites et favorise la differenciation en neurones. Par ailleurs, des analyses transcriptomiques par ARN-Seq realisees a partir des cellules differenciees demontrent que 10 % des transcrits detectes sont significativement deregules (p 1,5). En particulier, la majorite des marqueurs specifiques des different types neuronaux et des differentes couches du cortex (26/44) sont affectees, suggerant que miR-146a joue un role dans la differenciation et l’acquisition de l’identite des cellules neurales. Ces resultats sont coherents avec la desorganisation de l’architecture corticale et l’anomalie de formation des six differentes couches du cortex observes chez des patients autistes. Ils confirment le role de la sur-expression de miR-146a dans l’etiologie de la maladie.

Published
2017

43. Mutations in the mitochondrial glutamate carrierSLC25A22in neonatal epileptic encephalopathy with suppression bursts

Author

Francis Brunelle, Laurence Colleaux, Anna Kaminska, Perrine Plouin, Giuseppe Fiermonte, Luigi Palmieri, Annick Raas-Rothschild, Ferdinando Palmieri, Nathalie Boddaert, Florence Molinari, Olivier Dulac, and Arnold Munnich

Subjects
Male, medicine.medical_specialty, Microcephaly, Amino Acid Transport System X-AG, DNA Mutational Analysis, Molecular Sequence Data, Encephalopathy, Neonatal onset, medicine.disease_cause, Mitochondrial Membrane Transport Proteins, Infant, Newborn, Diseases, Mitochondrial Proteins, Epilepsy, Internal medicine, Genetics, Humans, Medicine, Family, Ictal, Genetics (clinical), Mutation, Base Sequence, business.industry, Infant, Newborn, Glutamate receptor, Membrane Transport Proteins, medicine.disease, Hypotonia, Mitochondria, Pedigree, Endocrinology, Female, medicine.symptom, business
Abstract

Neonatal epileptic encephalopathies with suppression bursts (SBs) are very severe and relatively rare diseases characterized by neonatal onset of seizures, interictal electroencephalogram (EEG) with SB pattern and very poor neurological outcome or death. Their etiology remains elusive but they are occasionally caused by metabolic diseases or malformations. Studying an Arab Muslim Israeli consanguineous family, with four affected children presenting a severe neonatal epileptic encephalopathy, we have previously identified a mutation in the SLC25A22 gene encoding a mitochondrial glutamate transporter. In this report, we describe a novel SLC25A22 mutation in an unrelated patient born from first cousin Algerian parents and presenting severe epileptic encephalopathy characterized by an EEG with SB, hypotonia, microcephaly and abnormal electroretinogram. We showed that this patient carried a homozygous p.G236W SLC25A22 mutation which alters a highly conserved amino acid and completely abolishes the glutamate carrier's activity in vitro. Comparison of the clinical features of patients from both families suggests that SLC25A22 mutations are responsible for a novel clinically recognizable epileptic encephalopathy with SB.

Published
2009

44. Neurobehavioral Profile and Brain Imaging Study of the 22q13.3 Deletion Syndrome in Childhood

Author

Anne Philippe, Valérie Malan, M. Zilbovicius, Laurence Robel, Bernard Golse, Marie-Christine de Blois, Laurence Vaivre-Douret, Nathalie Boddaert, Laurent Danon-Boileau, Delphine Héron, Arnold Munnich, and Laurence Colleaux

Subjects
Diagnostic Imaging, Male, Heterozygote, medicine.medical_specialty, Sensory processing, Chromosomes, Human, Pair 22, Developmental Disabilities, medicine.medical_treatment, 22q13 deletion syndrome, Neuropsychological Tests, Corpus callosum, Speech Disorders, Cohort Studies, Neurodevelopmental disorder, Neuroimaging, Intellectual Disability, medicine, OMIM : Online Mendelian Inheritance in Man, Humans, Psychology, Child, Psychiatry, Brain Diseases, business.industry, Prognosis, medicine.disease, Magnetic Resonance Imaging, Hypotonia, Child, Preschool, Positron-Emission Tomography, Pediatrics, Perinatology and Child Health, Autism, Female, Chromosome Deletion, Psychomotor Disorders, medicine.symptom, Cognition Disorders, business, Neuroscience
Abstract

OBJECTIVE. The 22q13.3 deletion syndrome (Online Mendelian Inheritance in Man No. 606232) is a neurodevelopmental disorder that includes hypotonia, severely impaired development of speech and language, autistic-like behavior, and minor dysmorphic features. Although the number of reported cases is increasing, the 22q13.3 deletion remains underdiagnosed because of failure in recognizing the clinical phenotype and detecting the 22qter deletion by routine chromosome analyses. Our goal is to contribute to the description of the neurobehavioral phenotype and brain abnormalities of this microdeletional syndrome. METHODS. We assessed neuromotor, sensory, language, communication, and social development and performed cerebral MRI and study of regional cerebral blood flow measured by positron emission tomography in 8 children carrying the 22q13.3 deletion. RESULTS. Despite variability in expression and severity, the children shared a common developmental profile characterized by hypotonia, sleep disorders, and poor response to their environment in early infancy; expressive language deficit contrasting with emergence of social reciprocity from ages ∼3 to 5 years; sensory processing dysfunction; and neuromotor disorders. Brain MRI findings were normal or showed a thin or morphologically atypical corpus callosum. Positron emission tomography study detected a localized dysfunction of the left temporal polar lobe and amygdala hypoperfusion. CONCLUSIONS. The developmental course of the 22q13.3 deletion syndrome belongs to pervasive developmental disorders but is distinct from autism. An improved description of the natural history of this syndrome should help in recognizing this largely underdiagnosed condition.

Published
2008

45. A nonsense variant in HERC1 is associated with intellectual disability, megalencephaly, thick corpus callosum and cerebellar atrophy

Author

Laurence Colleaux, Arnold Munich, Isabelle Desguerre, Taiane Schneider, Florine Verny, Valérie Cormier-Daire, Sébastien Moutton, Jose Luis Rosa, Marlène Rio, Lam Son Nguyen, Nathalie Boddaert, Karine Siquier-Pernet, 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 Génétique Médicale [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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5), 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], and CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)

Subjects
0301 basic medicine, Proband, Male, Adolescent, media_common.quotation_subject, Ubiquitin-Protein Ligases, Nonsense, Molecular Sequence Data, Short Report, Corpus Callosum, 03 medical and health sciences, Tuberous sclerosis, Cerebellum, Intellectual Disability, Intellectual disability, Genetics, medicine, Guanine Nucleotide Exchange Factors, Humans, Genetic Predisposition to Disease, Megalencephaly, Child, Genetics (clinical), PI3K/AKT/mTOR pathway, ComputingMilieux_MISCELLANEOUS, media_common, biology, Base Sequence, Infant, Newborn, medicine.disease, Ubiquitin ligase, Pedigree, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Codon, Nonsense, Child, Preschool, biology.protein, Cancer research, Cerebellar atrophy, Female, Atrophy
Abstract

Megalencephaly is a congenital condition characterized by severe overdeveloped brain size. This phenotype is often caused by mutations affecting the RTK/PI3K/mTOR (receptor tyrosine kinase-phosphatidylinositol-3-kinase-AKT) signaling and its downstream pathway of mammalian target of rapamycin (mTOR). Here, using a whole-exome sequencing in a Moroccan consanguineous family, we show that a novel autosomal-recessive neurological condition characterized by megalencephaly, thick corpus callosum and severe intellectual disability is caused by a homozygous nonsense variant in the HERC1 gene. Assessment of the primary skin fibroblast from the proband revealed complete absence of the HERC1 protein. HERC1 is an ubiquitin ligase that interacts with tuberous sclerosis complex 2, an upstream negative regulator of the mTOR pathway. Our data further emphasize the role of the mTOR pathway in the regulation of brain development and the power of next-generation sequencing technique in elucidating the genetic etiology of autosomal-recessive disorders and suggest that HERC1 defect might be a novel cause of autosomal-recessive syndromic megalencephaly.

Published
2015

46. Contiguous mutation syndrome in the era of high-throughput sequencing

Author

Maéva, Langouët, Karine, Siquier-Pernet, Sylvia, Sanquer, Christine, Bole-Feysot, Patrick, Nitschke, Nathalie, Boddaert, Arnold, Munnich, Grazia M S, Mancini, Robert, Barouki, Jeanne, Amiel, and Laurence, Colleaux

Subjects
AP4 deficiency syndrome, obesity, zinc-α2-glycoprotein, Original Articles, intellectual deficiency, whole-exome sequencing
Abstract

We investigated two siblings, born to consanguineous parents, with neurological features reminiscent of adaptor protein complex 4 (AP4) deficiency, an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity, severe intellectual disability speech delay, microcephaly, and growth retardation. Yet, both children also presented with early onset obesity. Whole-exome sequencing identified two homozygous substitutions in two genes 170 kb apart on 7q22.1: a c.1137+1G>T splice mutation in AP4M1 previously described in a familial case of AP4-deficiency syndrome and the AZGP1 c.595A>T missense variant. Haplotyping analysis indicated a founder effect of the AP4M1 mutation, whereas the AZGP1 mutation arose more recently in our family. AZGP1 encodes an adipokine that stimulate lipolysis in adipocytes and regulates body weight in mice. We propose that the siblings' phenotype results from the combined effects of mutations in both AP4M1 and AZGP1 that account for the neurological signs and the morbid obesity of early onset, respectively. Contiguous gene syndromes are the consequence of loss of two or more adjacent genes sensible to gene dosage and the phenotype reflects a combination of endophenotypes. We propose to broaden this concept to phenotypes resulting from independent mutations in two genetically linked genes causing a contiguous mutation syndrome.

Published
2014

47. Human Slack potassium channel mutations increase positive cooperativity between individual channels

Author

Jenny C. Taylor, Laurence Colleaux, Leonard K. Kaczmarek, Giulia Barcia, Hilary C. Martin, Jack Kronengold, Rima Nabbout, Imran H. Quraishi, Grace Kim, Edward Blair, Olivier Dulac, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, University of Oxford [Oxford], Centre de référence des épilepsies rares [CHU Pitié-Salpêtrière], Unité fonctionnelle d'épilepsie [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-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)-IFR70-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)-Service de Neurologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département de Neuropédiatrie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Departments of pharmacology and molecular biophysics and biochemistry [New Haven], Yale University School of Medicine, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR70-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)-Service de Neurologie [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (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), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]

Subjects
Potassium Channels, Mutant, Mutation, Missense, Gene Expression, Nerve Tissue Proteins, Gating, Potassium Channels, Sodium-Activated, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Article, Xenopus laevis, medicine, Animals, Humans, Point Mutation, lcsh:QH301-705.5, Ion channel, Cells, Cultured, Genetics, Mutation, Epilepsy, Chemistry, Point mutation, Infant, Newborn, Cooperative binding, Infant, Potassium channel, Rats, lcsh:Biology (General), [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, Biophysics, Communication channel
Abstract

Summary: Disease-causing mutations in ion channels generally alter intrinsic gating properties such as activation, inactivation, and voltage dependence. We examined nine different mutations of the KCNT1 (Slack) Na+-activated K+ channel that give rise to three distinct forms of epilepsy. All produced many-fold increases in current amplitude compared to the wild-type channel. This could not be accounted for by increases in the intrinsic open probability of individual channels. Rather, greatly increased opening was a consequence of cooperative interactions between multiple channels in a patch. The degree of cooperative gating was much greater for all of the mutant channels than for the wild-type channel, and could explain increases in current even in a mutant with reduced unitary conductance. We also found that the same mutation gave rise to different forms of epilepsy in different individuals. Our findings indicate that a major consequence of these mutations is to alter channel-channel interactions. : Slack KCNT1 channels regulate how neurons respond to sustained stimulation. Kim et al. characterized nine KCNT1 mutations found in epilepsy patients with severe intellectual disabilities and showed that, in isolation, channel behavior is unaltered. However, in groups, mutant channels interact with each other abnormally, increasing current that flows through the channels.

Published
2014

48. Unusual phenotype with progressive vertebral fusion in a girl with an apparently balanced t(10;20)(p11;p13) translocation

Author

Laurence Colleaux, Nicole Philip, Anne Moncla, Marie Geneviève Mattei, Chantal Missirian, Tania Attié-Bitach, Sabine Sigaudy, and G. Bollini

Subjects
0303 health sciences, Mutation, medicine.diagnostic_test, Translocation Breakpoint, Chromosomal translocation, Anatomy, Biology, medicine.disease_cause, Vertebra, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Vertebral fusion, Genetics, medicine, Chromosome 20, Noggin, 030217 neurology & neurosurgery, Genetics (clinical), 030304 developmental biology, Fluorescence in situ hybridization
Abstract

We report the case of a girl presenting with an unusual form of multiple joint fusion. Skeletal abnormalities consisted of radioulnar synostosis and vertebral fusions without any carpal, digital or tarsal involvement, and broad ribs and clavicles. Spinal X-rays were available from age 4 to 21, demonstrating that the spinal involvement was progressive and led to a complete anterior and lateral fusion of vertebrae. A complete sequencing of the NOGGIN gene failed to find any mutation. In addition, this girl was carrier of an apparently balanced reciprocal translocation t(10;20)(p11;p13). We investigated the role of the BMP2A gene as a potential candidate gene. Fluorescence in situ hybridization with YAC probes from chromosome 20 showed that the BMP2A gene was not disrupted by the translocation breakpoint.

Published
2005

49. Impaired Mitochondrial Glutamate Transport in Autosomal Recessive Neonatal Myoclonic Epilepsy

Author

Luigi Palmieri, Ziva Ben-Neriah, Arnold Munnich, Florence Molinari, Férechté Encha-Razavi, Pierre Rustin, Tania Attié-Bitach, Marlène Rio, Annick Raas-Rothschild, Michel Vekemans, Giuseppe Fiermonte, Noman Kadhom, Laurence Colleaux, Ferdinando Palmieri, Aix Marseille Université (AMU), The Chaim Sheba Medical Center [Tel Hashomer, Israel], Handicaps génétiques de l'enfant (Inserm U393), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Cytogénétique et Embryologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Social Robotics Laboratory, University of Freiburg, Freiburg im Breisgau, Università degli studi di Bari Aldo Moro (UNIBA), Department of Genetics, Hadassah University Hospital, Hadassah University Hospital, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Service de Génétique Médicale [CHU Necker], Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Università degli studi di Bari, CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Mitochondrial carrier, medicine.medical_specialty, Amino Acid Transport System X-AG, Glutamic Acid, Epilepsies, Myoclonic, Neonatal onset, Mitochondrion, Biology, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Myoclonic Epilepsies, Mutant protein, Report, Internal medicine, Genetics, medicine, Humans, Missense mutation, Genetics(clinical), Genetics (clinical), 030304 developmental biology, 0303 health sciences, Glutamate receptor, Electroencephalography, Glutamic acid, Glutamic Acid metabolism, medicine.disease, Mitochondria, Endocrinology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, Karyotyping, Myoclonic epilepsy, Female, 030217 neurology & neurosurgery
Abstract

International audience; Severe neonatal epilepsies with suppression-burst pattern are epileptic syndromes with either neonatal onset or onset during the first months of life. These disorders are characterized by a typical electroencephalogram pattern-namely, suppression burst, in which higher-voltage bursts of slow waves mixed with multifocal spikes alternate with isoelectric suppression phases. Here, we report the genetic mapping of an autosomal recessive form of this condition to chromosome 11p15.5 and the identification of a missense mutation (p.Pro206Leu) in the gene encoding one of the two mitochondrial glutamate/H + symporters (SLC25A22, also known as "GC1"). The mutation co-segregated with the disease and altered a highly conserved amino acid. Functional analyses showed that glutamate oxidation in cultured skin fibroblasts from patients was strongly defective. Further studies in reconstituted proteo-liposomes showed defective [ 14 C]glutamate uniport and [ 14 C]glutamate/glutamate exchange by mutant protein. Moreover , expression studies showed that, during human development, SLC25A22 is specifically expressed in the brain, within territories proposed to contribute to the genesis and control of myoclonic seizures. These findings provide the first direct molecular link between glutamate mitochondrial metabolism and myoclonic epilepsy and suggest potential insights into the pathophysiological bases of severe neonatal epilepsies with suppression-burst pattern.

Published
2005

50. Genome-wide screening using automated fluorescent genotyping to detect cryptic cytogenetic abnormalities in children with idiopathic syndromic mental retardation

Author

Florence Molinari, M. Le Merrer, Odile Raoul, Nigel P. Carter, Laurence Colleaux, Richard Redon, Valérie Cormier-Daire, Delphine Bacq, Arnold Munnich, Jeanne Amiel, Marlène Rio, Marguerite Prieur, Damien Sanlaville, Michel Vekemans, Guntram Borck, M-C de Blois, and Stanislas Lyonnet

Subjects
Genetics, 0303 health sciences, medicine.medical_specialty, education.field_of_study, 030305 genetics & heredity, Population, Cytogenetics, Chromosomal rearrangement, Biology, Subtelomere, medicine.disease, Genome, Uniparental disomy, 03 medical and health sciences, medicine, Microsatellite, education, Genotyping, Genetics (clinical), 030304 developmental biology
Abstract

Mental retardation (MR) is the most common developmental disability, affecting approximately 2% of the population. The causes of MR are diverse and poorly understood, but chromosomal rearrangements account for 4-28% of cases, and duplications/deletions smaller than 5 Mb are known to cause syndromic MR. We have previously developed a strategy based on automated fluorescent microsatellite genotyping to test for telomere integrity. This strategy detected about 10% of cryptic subtelomeric rearrangements in patients with idiopathic syndromic MR. Because telomere screening is a first step toward the goal of analyzing the entire genome for chromosomal rearrangements in MR, we have extended our strategy to 400 markers evenly distributed along the chromosomes to detect interstitial anomalies. Among 97 individuals tested, three anomalies were found: two deletions (one in three siblings) and one parental disomy. These results emphasize the value of a genome-wide microsatellite scan for the detection of interstitial aberrations and demonstrate that automated genotyping is a sensitive method that not only detects small interstitial rearrangements and their parental origin but also provides a unique opportunity to detect uniparental disomies. This study will hopefully contribute to the delineation of new contiguous gene syndromes and the identification of new imprinted regions.

Published
2004

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