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1. Expression of placental CD146 is dysregulated by prenatal alcohol exposure and contributes in cortical vasculature development and positioning of vessel-associated oligodendrocytes

Author

Camille Sautreuil, Maryline Lecointre, Jessica Dalmasso, Alexis Lebon, Matthieu Leuillier, François Janin, Matthieu Lecuyer, Soumeya Bekri, Stéphane Marret, Annie Laquerrière, Carole Brasse-Lagnel, Sophie Gil, and Bruno J. Gonzalez

Subjects
fetal alcohol syndrome, angiogenesis, neurovascular development, neuroplacentology, biomarker, diagnosis, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Recent data showed that prenatal alcohol exposure (PAE) impairs the “placenta–brain” axis controlling fetal brain angiogenesis in human and preclinical models. Placental growth factor (PlGF) has been identified as a proangiogenic messenger between these two organs. CD146, a partner of the VEGFR-1/2 signalosome, is involved in placental angiogenesis and exists as a soluble circulating form. The aim of the present study was to investigate whether placental CD146 may contribute to brain vascular defects described in fetal alcohol spectrum disorder. At a physiological level, quantitative reverse transcription polymerase chain reaction experiments performed in human placenta showed that CD146 is expressed in developing villi and that membrane and soluble forms of CD146 are differentially expressed from the first trimester to term. In the mouse placenta, a similar expression pattern of CD146 was found. CD146 immunoreactivity was detected in the labyrinth zone and colocalized with CD31-positive endothelial cells. Significant amounts of soluble CD146 were quantified by ELISA in fetal blood, and the levels decreased after birth. In the fetal brain, the membrane form of CD146 was the majority and colocalized with microvessels. At a pathophysiological level, PAE induced marked dysregulation of CD146 expression. The soluble form of CD146 decreased in both placenta and fetal blood, whereas it increased in the fetal brain. Similarly, the expression of several members of the CD146 signalosome, such as VEGFR2 and PSEN, was differentially impaired between the two organs by PAE. At a functional level, targeted repression of placental CD146 by in utero electroporation (IUE) of CRISPR/Cas9 lentiviral plasmids resulted in (i) a decrease in cortical vessel density, (ii) a loss of radial vascular organization, and (iii) a reduced density of oligodendrocytes. Statistical analysis showed that the more the vasculature was impaired, the more the cortical oligodendrocyte density was reduced. Altogether, these data support that placental CD146 contributes to the proangiogenic “placenta–brain” axis and that placental CD146 dysfunction contributes to the cortical oligo-vascular development. Soluble CD146 would represent a promising placental biomarker candidate representative of alcohol-induced neurovascular defects in neonates, as recently suggested by PlGF (patents WO2016207253 and WO2018100143).

Published
2024
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2. Oligodendrocyte lineage is severely affected in human alcohol-exposed foetuses

Author

Florent Marguet, Mélanie Brosolo, Gaëlle Friocourt, Fanny Sauvestre, Pascale Marcorelles, Céline Lesueur, Stéphane Marret, Bruno J. Gonzalez, and Annie Laquerrière

Subjects
Oligodendrocyte precursors, PDGFR-α, Olig2, Myelination defects, Human foetal brain, Foetal alcohol syndrome, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Prenatal alcohol exposure is a major cause of neurobehavioral disabilities. MRI studies in humans have shown that alcohol is associated with white matter microstructural anomalies but these studies focused on myelin abnormalities only after birth. Only one of these studies evaluated oligodendrocyte lineage, but only for a short period during human foetal life. As data are lacking in humans and alcohol is known to impair oligodendrocyte differentiation in rodents, the present study aimed to compare by immunohistochemistry the oligodendrocyte precursor cells expressing PDGFR-α and immature premyelinating/mature oligodendrocytes expressing Olig2 in the ganglionic eminences and the frontal cortex of 14 human foetuses exposed to alcohol from 15 to 37 weeks’ gestation with age-matched controls. The human brains used in this study were obtained at the time of foetal autopsies for medical termination of pregnancy, in utero or post-natal early death. Before birth, PDGFR-α expression was strongly increased in the ganglionic eminences and the cortex of all foetuses exposed to alcohol except at the earliest stage. No massive generation of Olig2 immunoreactive cells was identified in the ganglionic eminences until the end of pregnancy and the density of Olig2-positive cells within the cortex was consistently lower in foetuses exposed to alcohol than in controls. These antenatal data from humans provides further evidence of major oligodendrocyte lineage impairment at specific and key stages of brain development upon prenatal alcohol exposure including defective or delayed generation and maturation of oligodendrocyte precursors.

Published
2022
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3. A postzygotic de novo NCDN mutation identified in a sporadic FTLD patient results in neurochondrin haploinsufficiency and altered FUS granule dynamics

Author

Gaël Nicolas, Myriam Sévigny, François Lecoquierre, Florent Marguet, Andréanne Deschênes, Maria Carment del Pelaez, Sébastien Feuillette, Anaïs Audebrand, Magalie Lecourtois, Stéphane Rousseau, Anne-Claire Richard, Kévin Cassinari, Vincent Deramecourt, Charles Duyckaerts, Anne Boland, Jean-François Deleuze, Vincent Meyer, Jordi Clarimon Echavarria, Ellen Gelpi, Haruhiko Akiyama, Masato Hasegawa, Ito Kawakami, Tsz H. Wong, Jeroen G. J. Van Rooij, John C. Van Swieten, Dominique Campion, Paul A. Dutchak, David Wallon, Flavie Lavoie-Cardinal, Annie Laquerrière, Anne Rovelet-Lecrux, and Chantelle F. Sephton

Subjects
FUS (fused in sarcoma), Frontotemporal dementia (FTD), NCDN (neurochondrin), Norbin, Genetic variant, De novo mutation, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Frontotemporal dementia (FTD) is a heterogeneous clinical disorder characterized by progressive abnormalities in behavior, executive functions, personality, language and/or motricity. A neuropathological subtype of FTD, frontotemporal lobar degeneration (FTLD)-FET, is characterized by protein aggregates consisting of the RNA-binding protein fused in sarcoma (FUS). The cause of FTLD-FET is not well understood and there is a lack of genetic evidence to aid in the investigation of mechanisms of the disease. The goal of this study was to identify genetic variants contributing to FTLD-FET and to investigate their effects on FUS pathology. We performed whole-exome sequencing on a 50-year-old FTLD patient with ubiquitin and FUS-positive neuronal inclusions and unaffected parents, and identified a de novo postzygotic nonsense variant in the NCDN gene encoding Neurochondrin (NCDN), NM_014284.3:c.1206G > A, p.(Trp402*). The variant was associated with a ~ 31% reduction in full-length protein levels in the patient’s brain, suggesting that this mutation leads to NCDN haploinsufficiency. We examined the effects of NCDN haploinsufficiency on FUS and found that depleting primary cortical neurons of NCDN causes a reduction in the total number of FUS-positive cytoplasmic granules. Moreover, we found that these granules were significantly larger and more highly enriched with FUS. We then examined the effects of a loss of FUS function on NCDN in neurons and found that depleting cells of FUS leads to a decrease in NCDN protein and mRNA levels. Our study identifies the NCDN protein as a likely contributor of FTLD-FET pathophysiology. Moreover, we provide evidence for a negative feedback loop of toxicity between NCDN and FUS, where loss of NCDN alters FUS cytoplasmic dynamics, which in turn has an impact on NCDN expression.

Published
2022
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4. Prenatal Alcohol Exposure Impairs the Placenta–Cortex Transcriptomic Signature, Leading to Dysregulation of Angiogenic Pathways

Author

Camille Sautreuil, Maryline Lecointre, Céline Derambure, Carole Brasse-Lagnel, Philippe Leroux, Annie Laquerrière, Gaël Nicolas, Sophie Gil, Daniel D. Savage, Stéphane Marret, Florent Marguet, Anthony Falluel-Morel, and Bruno J. Gonzalez

Subjects
FASD, neuroplacentology, neurovascular, neurodevelopment, diagnosis, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Although alcohol consumption during pregnancy is a major cause of behavioral and learning disabilities, most FASD infants are late- or even misdiagnosed due to clinician’s difficulties achieving early detection of alcohol-induced neurodevelopmental impairments. Neuroplacentology has emerged as a new field of research focusing on the role of the placenta in fetal brain development. Several studies have reported that prenatal alcohol exposure (PAE) dysregulates a functional placenta–cortex axis, which is involved in the control of angiogenesis and leads to neurovascular-related defects. However, these studies were focused on PlGF, a pro-angiogenic factor. The aim of the present study is to provide the first transcriptomic “placenta–cortex” signature of the effects of PAE on fetal angiogenesis. Whole mouse genome microarrays of paired placentas and cortices were performed to establish the transcriptomic inter-organ “placenta–cortex” signature in control and PAE groups at gestational day 20. Genespring comparison of the control and PAE signatures revealed that 895 and 1501 genes were only detected in one of two placenta–cortex expression profiles, respectively. Gene ontology analysis indicated that 107 of these genes were associated with vascular development, and String protein–protein interaction analysis showed that they were associated with three functional clusters. PANTHER functional classification analysis indicated that “intercellular communication” was a significantly enriched biological process, and 27 genes were encoded for neuroactive ligand/receptors interactors. Protein validation experiments involving Western blot for one ligand–receptor couple (Agt/AGTR1/2) confirmed the transcriptomic data, and Pearson statistical analysis of paired placentas and fetal cortices revealed a negative correlation between placental Atg and cortical AGTR1, which was significantly impacted by PAE. In humans, a comparison of a 38WG control placenta with a 36WG alcohol-exposed placenta revealed low Agt immunolabeling in the syncytiotrophoblast layer of the alcohol case. In conclusion, this study establishes the first transcriptomic placenta–cortex signature of a developing mouse. The data show that PAE markedly unbalances this inter-organ signature; in particular, several ligands and/or receptors involved in the control of angiogenesis. These data support that PAE modifies the existing communication between the two organs and opens new research avenues regarding the impact of placental dysfunction on the neurovascular development of fetuses. Such a signature would present a clinical value for early diagnosis of brain defects in FASD.

Published
2023
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5. Muscle metabolic remodelling patterns in Duchenne muscular dystrophy revealed by ultra-high-resolution mass spectrometry imaging

Author

Ivana Dabaj, Justine Ferey, Florent Marguet, Vianney Gilard, Carole Basset, Youssef Bahri, Anne-Claire Brehin, Catherine Vanhulle, France Leturcq, Stéphane Marret, Annie Laquerrière, Isabelle Schmitz-Afonso, Carlos Afonso, Soumeya Bekri, and Abdellah Tebani

Subjects
Medicine, Science
Abstract

Abstract Duchenne muscular dystrophy (DMD) is a common and severe X-linked myopathy, characterized by muscle degeneration due to altered or absent dystrophin. DMD has no effective cure, and the underlying molecular mechanisms remain incompletely understood. The aim of this study is to investigate the metabolic changes in DMD using mass spectrometry-based imaging. Nine human muscle biopsies from DMD patients and nine muscle biopsies from control individuals were subjected to untargeted MSI using matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometry. Both univariate and pattern recognition techniques have been used for data analysis. This study revealed significant changes in 34 keys metabolites. Seven metabolites were decreased in the Duchenne biopsies compared to control biopsies including adenosine triphosphate, and glycerophosphocholine. The other 27 metabolites were increased in the Duchenne biopsies, including sphingomyelin, phosphatidylcholines, phosphatidic acids and phosphatidylserines. Most of these dysregulated metabolites are tightly related to energy and phospholipid metabolism. This study revealed a deep metabolic remodelling in phospholipids and energy metabolism in DMD. This systems-based approach enabled exploring the metabolism in DMD in an unprecedented holistic and unbiased manner with hypothesis-free strategies.

Published
2021
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6. Prenatal alcohol exposure is a leading cause of interneuronopathy in humans

Author

Florent Marguet, Gaëlle Friocourt, Mélanie Brosolo, Fanny Sauvestre, Pascale Marcorelles, Céline Lesueur, Stéphane Marret, Bruno J. Gonzalez, and Annie Laquerrière

Subjects
GABAergic system defects, Human foetal/neonatal brain, Foetal alcohol syndrome, Immunohistochemistry, Vascular interneuron migration, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Alcohol affects multiple neurotransmitter systems, notably the GABAergic system and has been recognised for a long time as particularly damaging during critical stages of brain development. Nevertheless, data from the literature are most often derived from animal or in vitro models. In order to study the production, migration and cortical density disturbances of GABAergic interneurons upon prenatal alcohol exposure, we performed immunohistochemical studies by means of the proliferation marker Ki67, GABA and calretinin antibodies in the frontal cortical plate of 17 foetal and infant brains antenatally exposed to alcohol, aged 15 weeks’ gestation to 22 postnatal months and in the ganglionic eminences and the subventricular zone of the dorsal telencephalon until their regression, i.e., 34 weeks’ gestation. Results were compared with those obtained in 17 control brains aged 14 weeks of gestation to 35 postnatal months. We also focused on interneuron vascular migration along the cortical microvessels by confocal microscopy with double immunolabellings using Glut1, GABA and calretinin. Semi-quantitative and quantitative analyses of GABAergic and calretininergic interneuron density allowed us to identify an insufficient and delayed production of GABAergic interneurons in the ganglionic eminences during the two first trimesters of the pregnancy and a delayed incorporation into the laminar structures of the frontal cortex. Moreover, a mispositioning of GABAergic and calretininergic interneurons persisted throughout the foetal life, these cells being located in the deep layers instead of the superficial layers II and III. Moreover, vascular migration of calretininergic interneurons within the cortical plate was impaired, as reflected by low numbers of interneurons observed close to the cortical perforating vessel walls that may in part explain their abnormal intracortical distribution. Our results are globally concordant with those previously obtained in mouse models, in which alcohol has been shown to induce an interneuronopathy by affecting interneuron density and positioning within the cortical plate, and which could account for the neurological disabilities observed in children with foetal alcohol disorder spectrum.

Published
2020
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7. Cell-free DNA and circulating TERT promoter mutation for disease monitoring in newly-diagnosed glioblastoma

Author

Maxime Fontanilles, Florent Marguet, Ludivine Beaussire, Nicolas Magne, Louis-Ferdinand Pépin, Cristina Alexandru, Isabelle Tennevet, Chantal Hanzen, Olivier Langlois, Fabrice Jardin, Annie Laquerrière, Nasrin Sarafan-Vasseur, Fréderic Di Fiore, and Florian Clatot

Subjects
Glioblastoma, Cell-free DNA, Circulating tumor DNA, TERT promoter mutation, Liquid biopsy, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract The clinical implications of plasmatic cell-free and tumor DNA (cfDNA and ctDNA) are challenging in glioblastoma. This prospective study included 52 consecutive newly diagnosed glioblastoma (n = 49) or gliosarcoma (n = 3) patients treated with concomitant temozolomide and radiotherapy (RT-TMZ), followed by a TMZ maintenance phase. Plasma samples were collected at baseline, before RT-TMZ (pre-RT-TMZ) and at the end of adjuvant TMZ, or at the time of progression in cases of progressive disease (PD). The cfDNA concentration was measured with a fluorometric method, and ctDNA was detected using targeted droplet digital PCR. The main objectives were to analyze the associations between cfDNA and ctDNA measurements during the course of treatment with PD and survival. There was a significant decrease in median cfDNA concentration from baseline to pre-RT-TMZ—19.4 versus 9.7 ng/mL (p

Published
2020
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8. Foetal onset of EIF2B related disorder in two siblings: cerebellar hypoplasia with absent Bergmann glia and severe hypomyelination

Author

Aurélien Trimouille, Florent Marguet, Fanny Sauvestre, Eulalie Lasseaux, Fanny Pelluard, Marie-Laure Martin-Négrier, Claudio Plaisant, Caroline Rooryck, Didier Lacombe, Benoît Arveiler, Odile Boespflug-Tanguy, Sophie Naudion, and Annie Laquerrière

Subjects
Vanishing white matter disease, Foetal neuropathology, Whole exome sequencing, Diagnosis, Pathophysiology, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Bi-allelic pathogenic variants in genes of the EIF2B family are responsible for Childhood Ataxia with Central nervous system Hypomyelination/Vanishing White Matter disease, a progressive neurodegenerative disorder of the central white matter. Only seven molecularly proven cases with antenatal onset have been reported so far. We report for the first time the neuropathological findings obtained from two foetuses harbouring deleterious variants in the EIF2B5 gene who presented in utero growth retardation and microcephaly with simplified gyral pattern that led to a medical termination of the pregnancy at 27 and 32 weeks of gestation. Neuropathological examination confirmed microcephaly with delayed gyration, periventricular pseudo-cysts and severe cerebellar hypoplasia. Histologically, the cerebellar cortex was immature, the dentate nuclei were fragmented and myelin stains revealed almost no myelination of the infratentorial structures. Bergmann glia was virtually absent associated to a drastic decreased number of mature astrocytes in the cerebellar white matter, multiple nestin-positive immature astrocytes as well as increased numbers of PDGRFα-positive oligodendrocyte precursors. Whole exome sequencing performed in the two foetuses and their parents allowed the identification of two EIF2B5 compound heterozygous variants in the two foetuses: c.468C > G p.Ile156Met and c.1165G > A p.Val389Met, the parents being heterozygous carriers. These variants are absent in the genome Aggregation Database (gnomAD r2.0.2). Contrary to the variant Ile156Met already described in a patient with CACH syndrome, the variant p.Val389Met is novel and predicted to be deleterious using several softwares. Neuropathological findings further expand the phenotypic spectrum of the disease that very likely occurs during early gestation and may manifest from the second half of pregnancy by a severe impairment of cerebral and cerebellar development.

Published
2020
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9. Simultaneous detection of EGFR amplification and EGFRvIII variant using digital PCR-based method in glioblastoma

Author

Maxime Fontanilles, Florent Marguet, Philippe Ruminy, Carole Basset, Adrien Noel, Ludivine Beaussire, Mathieu Viennot, Pierre-Julien Viailly, Kevin Cassinari, Pascal Chambon, Doriane Richard, Cristina Alexandru, Isabelle Tennevet, Olivier Langlois, Frédéric Di Fiore, Annie Laquerrière, Florian Clatot, and Nasrin Sarafan-Vasseur

Subjects
Glioblastoma, Digital PCR, EGFR amplification, EGFRvIII variant, Cost-effectiveness, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Epidermal growth factor receptor (EGFR) amplification and EGFR variant III (EGFRvIII, deletion of exons 2–7) are of clinical interest for glioblastoma. The aim was to develop a digital PCR (dPCR)-based method using locked nucleic acid (LNA)-based hydrolysis probes, allowing the simultaneous detection of the EGFR amplification and EGFRvIII variant. Sixty-two patients were included. An exploratory cohort (n = 19) was used to develop the dPCR assay using three selected amplicons within the EGFR gene, targeting intron 1 (EGFR1), junction of exon 3 and intron 3 (EGFR2) and intron 22 (EGFR3). The copy number of EGFR was estimated by the relative quantification of EGFR1, EGFR2 and EGFR3 amplicon droplets compared to the droplets of a reference gene. EGFRvIII was identified by comparing the copy number of the EGFR2 amplicon to either the EGFR1 or EGFR3 amplicon. dPCR results were compared to fluorescence in situ hybridization (FISH) and next-generation sequencing for amplification; and to RT-PCR-based method for EGFRvIII. The dPCR assay was then tested in a validation cohort (n = 43). A total of 8/19 EGFR-amplified and 5/19 EGFRvIII-positive tumors were identified in the exploratory cohort. Compared to FISH, the EGFR3 dPCR assay detected all EGFR-amplified tumors (8/8, 100%) and had the highest concordance with the copy number estimation by NGS. The concordance between RT-PCR and dPCR was also 100% for detecting EGFRvIII using an absolute difference of 10.8 for the copy number between EGFR2 and EGFR3 probes. In the validation cohort, the sensitivity and specificity of dPCR using EGFR3 probes were 100% for the EGFR amplification detection compared to FISH (19/19). EGFRvIII was detected by dPCR in 8 EGFR-amplified patients and confirmed by RT-PCR. Compared to FISH, the EGFR2/EGFR3 dPCR assay was estimated with a one-half cost value. These results highlight that dPCR allowed the simultaneous detection of EGFR amplification and EGFRvIII for glioblastoma.

Published
2020
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10. Targeting the Urotensin II/UT G Protein-Coupled Receptor to Counteract Angiogenesis and Mesenchymal Hypoxia/Necrosis in Glioblastoma

Author

Vadim Le Joncour, Pierre-Olivier Guichet, Kleouforo-Paul Dembélé, Alexandre Mutel, Daniele Campisi, Nicolas Perzo, Laurence Desrues, Romain Modzelewski, Pierre-Olivier Couraud, Jérôme Honnorat, François-Xavier Ferracci, Florent Marguet, Annie Laquerrière, Pierre Vera, Pierre Bohn, Olivier Langlois, Fabrice Morin, Pierrick Gandolfo, and Hélène Castel

Subjects
glioblastoma, urotensin II, UT receptor, angiogenesis, necrosis, biased ligand, Biology (General), QH301-705.5
Abstract

Glioblastomas (GBMs) are the most common primary brain tumors characterized by strong invasiveness and angiogenesis. GBM cells and microenvironment secrete angiogenic factors and also express chemoattractant G protein-coupled receptors (GPCRs) to their advantage. We investigated the role of the vasoactive peptide urotensin II (UII) and its receptor UT on GBM angiogenesis and tested potential ligand/therapeutic options based on this system. On glioma patient samples, the expression of UII and UT increased with the grade with marked expression in the vascular and peri-necrotic mesenchymal hypoxic areas being correlated with vascular density. In vitro human UII stimulated human endothelial HUV-EC-C and hCMEC/D3 cell motility and tubulogenesis. In mouse-transplanted Matrigel sponges, mouse (mUII) and human UII markedly stimulated invasion by macrophages, endothelial, and smooth muscle cells. In U87 GBM xenografts expressing UII and UT in the glial and vascular compartments, UII accelerated tumor development, favored hypoxia and necrosis associated with increased proliferation (Ki67), and induced metalloproteinase (MMP)-2 and -9 expression in Nude mice. UII also promoted a “tortuous” vascular collagen-IV expressing network and integrin expression mainly in the vascular compartment. GBM angiogenesis and integrin αvβ3 were confirmed by in vivo99mTc-RGD tracer imaging and tumoral capture in the non-necrotic area of U87 xenografts in Nude mice. Peptide analogs of UII and UT antagonist were also tested as potential tumor repressor. Urotensin II-related peptide URP inhibited angiogenesis in vitro and failed to attract vascular and inflammatory components in Matrigel in vivo. Interestingly, the UT antagonist/biased ligand urantide and the non-peptide UT antagonist palosuran prevented UII-induced tubulogenesis in vitro and significantly delayed tumor growth in vivo. Urantide drastically prevented endogenous and UII-induced GBM angiogenesis, MMP, and integrin activations, associated with GBM tumoral growth. These findings show that UII induces GBM aggressiveness with necrosis and angiogenesis through integrin activation, a mesenchymal behavior that can be targeted by UT biased ligands/antagonists.

Published
2021
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11. A de novo variant in ADGRL2 suggests a novel mechanism underlying the previously undescribed association of extreme microcephaly with severely reduced sulcation and rhombencephalosynapsis

Author

Myriam Vezain, Matthieu Lecuyer, Marina Rubio, Valérie Dupé, Leslie Ratié, Véronique David, Laurent Pasquier, Sylvie Odent, Sophie Coutant, Isabelle Tournier, Laetitia Trestard, Homa Adle-Biassette, Denis Vivien, Thierry Frébourg, Bruno J Gonzalez, Annie Laquerrière, and Pascale Saugier-Veber

Subjects
ADGRL2, LPHN2, Adhesion-GPCR, Alpha-latrotoxin, Human extreme microcephaly, Rhombencephalosynapsis, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Extreme microcephaly and rhombencephalosynapsis represent unusual pathological conditions, each of which occurs in isolation or in association with various other cerebral and or extracerebral anomalies. Unlike microcephaly for which several disease-causing genes have been identified with different modes of inheritance, the molecular bases of rhombencephalosynapsis remain unknown and rhombencephalosynapsis presents mainly as a sporadic condition consistent with de novo dominant variations. We report for the first time the association of extreme microcephaly with almost no sulcation and rhombencephalosynapsis in a fœtus for which comparative patient-parent exome sequencing strategy revealed a heterozygous de novo missense variant in the ADGRL2 gene. ADGRL2 encodes latrophilin 2, an adhesion G-protein-coupled receptor whose exogenous ligand is α-latrotoxin. Adgrl2 immunohistochemistry and in situ hybridization revealed expression in the telencephalon, mesencephalon and rhombencephalon of mouse and chicken embryos. In human brain embryos and fœtuses, Adgrl2 immunoreactivity was observed in the hemispheric and cerebellar germinal zones, the cortical plate, basal ganglia, pons and cerebellar cortex. Microfluorimetry experiments evaluating intracellular calcium release in response to α-latrotoxin binding showed significantly reduced cytosolic calcium release in the fœtus amniocytes vs amniocytes from age-matched control fœtuses and in HeLa cells transfected with mutant ADGRL2 cDNA vs wild-type construct. Embryonic lethality was also observed in constitutive Adgrl2 −/− mice. In Adgrl2 +/− mice, MRI studies revealed microcephaly and vermis hypoplasia. Cell adhesion and wound healing assays demonstrated that the variation increased cell adhesion properties and reduced cell motility. Furthermore, HeLa cells overexpressing mutant ADGRL2 displayed a highly developed cytoplasmic F-actin network related to cytoskeletal dynamic modulation. ADGRL2 is the first gene identified as being responsible for extreme microcephaly with rhombencephalosynapsis. Increased cell adhesion, reduced cell motility and cytoskeletal dynamic alterations induced by the variant therefore represent a new mechanism responsible for microcephaly.

Published
2018
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12. In utero alcohol exposure exacerbates endothelial protease activity from pial microvessels and impairs GABA interneuron positioning

Author

Cécile Léger, Nicolas Dupré, Annie Laquerrière, Maryline Lecointre, Marion Dumanoir, François Janin, Michelle Hauchecorne, Maëlle Fabre, Sylvie Jégou, Thierry Frébourg, Carine Cleren, Philippe Leroux, Pascale Marcorelles, Carole Brasse-Lagnel, Stéphane Marret, Florent Marguet, and Bruno J. Gonzalez

Subjects
Fetal alcohol spectrum disorder, Neurovascular, Endothelial cells, GABA interneurons, Matrix metalloproteinase-9 (MMP-9), Tissue plasminogen activator (tPA), Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

In utero alcohol exposure can induce severe neurodevelopmental disabilities leading to long-term behavioral deficits. Because alcohol induces brain defects, many studies have focused on nervous cells. However, recent reports have shown that alcohol markedly affects cortical angiogenesis in both animal models and infants with fetal alcohol spectrum disorder (FASD). In addition, the vascular system is known to contribute to controlling gamma-aminobutyric acid (GABA)ergic interneuron migration in the developing neocortex. Thus, alcohol-induced vascular dysfunction may contribute to the neurodevelopmental defects in FASD. The present study aimed at investigating the effects of alcohol on endothelial activity of pial microvessels. Ex vivo experiments on cortical slices from mouse neonates revealed that in endothelial cells from pial microvessels acute alcohol exposure inhibits both glutamate-induced calcium mobilization and activities of matrix metalloproteinase-9 (MMP-9) and tissue plasminogen activator (tPA). The inhibitory effect of alcohol on glutamate-induced MMP-9 activity was abrogated in tPA-knockout and Grin1flox/VeCadcre mice suggesting that alcohol interacts through the endothelial NMDAR/tPA/MMP-9 vascular pathway. Contrasting with the effects from acute alcohol exposure, in mouse neonates exposed to alcohol in utero during the last gestational week, glutamate exacerbated both calcium mobilization and endothelial protease activities from pial microvessels. This alcohol-induced vascular dysfunction was associated with strong overexpression of the N-methyl-d-aspartate receptor subunit GluN1 and mispositioning of the Gad67-GFP interneurons that normally populate the superficial cortical layers. By comparing several human control fetuses with a fetus chronically exposed to alcohol revealed that alcohol exposure led to mispositioning of the calretinin-positive interneurons, whose density was decreased in the superficial cortical layers II-III and increased in deepest layers. This study provides the first mechanistic and functional evidence that alcohol impairs glutamate-regulated activity of pial microvessels. Endothelial dysfunction is characterized by altered metalloproteinase activity and interneuron mispositioning, which was also observed in a fetus with fetal alcohol syndrome. These data suggest that alcohol-induced endothelial dysfunction may contribute in ectopic cortical GABAergic interneurons, that has previously been described in infants with FASD.

Published
2020
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13. Basal ganglia involvement in ARX patients: The reason for ARX patients very specific grasping?

Author

Aurore Curie, Gaëlle Friocourt, Vincent des Portes, Alice Roy, Tatjana Nazir, Amandine Brun, Anne Cheylus, Pascale Marcorelles, Kalliroi Retzepi, Nasim Maleki, Gérald Bussy, Yves Paulignan, Anne Reboul, Danielle Ibarrola, Jian Kong, Nouchine Hadjikhani, Annie Laquerrière, and Randy L. Gollub

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract

The ARX (Aristaless Related homeoboX) gene was identified in 2002 as responsible for XLAG syndrome, a lissencephaly characterized by an almost complete absence of cortical GABAergic interneurons, and for milder forms of X-linked Intellectual Disability (ID) without apparent brain abnormalities. The most frequent mutation found in the ARX gene, a duplication of 24 base pairs (c.429_452dup24) in exon 2, results in a recognizable syndrome in which patients present ID without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip, described as developmental Limb Kinetic Apraxia (LKA).In this study, we first present ARX expression during human fetal brain development showing that it is strongly expressed in GABAergic neuronal progenitors during the second and third trimester of pregnancy. We show that although ARX expression strongly decreases towards the end of gestation, it is still present after birth in some neurons of the basal ganglia, thalamus and cerebral cortex, suggesting that ARX also plays a role in more mature neuron functioning. Then, using morphometric brain MRI in 13 ARX patients carrying c.429_452dup24 mutation and in 13 sex- and age-matched healthy controls, we show that ARX patients have a significantly decreased volume of several brain structures including the striatum (and more specifically the caudate nucleus), hippocampus and thalamus as well as decreased precentral gyrus cortical thickness. We observe a significant correlation between caudate nucleus volume reduction and motor impairment severity quantified by kinematic parameter of precision grip.As basal ganglia are known to regulate sensorimotor processing and are involved in the control of precision gripping, the combined decrease in cortical thickness of primary motor cortex and basal ganglia volume in ARX dup24 patients is very likely the anatomical substrate of this developmental form of LKA. Keywords: ARX, Human brain development, Intellectual disability, Morphometric MRI, Kinematic, Limb Kinetic Apraxia

Published
2018
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14. Integrative Metabolomics Reveals Deep Tissue and Systemic Metabolic Remodeling in Glioblastoma

Author

Vianney Gilard, Justine Ferey, Florent Marguet, Maxime Fontanilles, Franklin Ducatez, Carine Pilon, Céline Lesueur, Tony Pereira, Carole Basset, Isabelle Schmitz-Afonso, Frédéric Di Fioré, Annie Laquerrière, Carlos Afonso, Stéphane Derrey, Stéphane Marret, Soumeya Bekri, and Abdellah Tebani

Subjects
glioblastoma, high-grade glioma, brain tumor, neuro-oncology, metabolomics, omics, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

(1) Background: Glioblastoma is the most common malignant brain tumor in adults. Its etiology remains unknown in most cases. Glioblastoma pathogenesis consists of a progressive infiltration of the white matter by tumoral cells leading to progressive neurological deficit, epilepsy, and/or intracranial hypertension. The mean survival is between 15 to 17 months. Given this aggressive prognosis, there is an urgent need for a better understanding of the underlying mechanisms of glioblastoma to unveil new diagnostic strategies and therapeutic targets through a deeper understanding of its biology. (2) Methods: To systematically address this issue, we performed targeted and untargeted metabolomics-based investigations on both tissue and plasma samples from patients with glioblastoma. (3) Results: This study revealed 176 differentially expressed lipids and metabolites, 148 in plasma and 28 in tissue samples. Main biochemical classes include phospholipids, acylcarnitines, sphingomyelins, and triacylglycerols. Functional analyses revealed deep metabolic remodeling in glioblastoma lipids and energy substrates, which unveils the major role of lipids in tumor progression by modulating its own environment. (4) Conclusions: Overall, our study demonstrates in situ and systemic metabolic rewiring in glioblastoma that could shed light on its underlying biological plasticity and progression to inform diagnosis and/or therapeutic strategies.

Published
2021
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15. Diagnosis and Management of Glioblastoma: A Comprehensive Perspective

Author

Vianney Gilard, Abdellah Tebani, Ivana Dabaj, Annie Laquerrière, Maxime Fontanilles, Stéphane Derrey, Stéphane Marret, and Soumeya Bekri

Subjects
glioblastoma, molecular pathology, omics, pathogenesis, personalized therapies, Medicine
Abstract

Glioblastoma is the most common malignant brain tumor in adults. The current management relies on surgical resection and adjuvant radiotherapy and chemotherapy. Despite advances in our understanding of glioblastoma onset, we are still faced with an increased incidence, an altered quality of life and a poor prognosis, its relapse and a median overall survival of 15 months. For the past few years, the understanding of glioblastoma physiopathology has experienced an exponential acceleration and yielded significant insights and new treatments perspectives. In this review, through an original R-based literature analysis, we summarize the clinical presentation, current standards of care and outcomes in patients diagnosed with glioblastoma. We also present the recent advances and perspectives regarding pathophysiological bases as well as new therapeutic approaches such as cancer vaccination and personalized treatments.

Published
2021
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16. PLGF, a placental marker of fetal brain defects after in utero alcohol exposure

Author

Matthieu Lecuyer, Annie Laquerrière, Soumeya Bekri, Céline Lesueur, Yasmina Ramdani, Sylvie Jégou, Arnaud Uguen, Pascale Marcorelles, Stéphane Marret, and Bruno J. Gonzalez

Subjects
Fetal alcohol exposure, Angiogenesis, Cortex, Placenta, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Most children with in utero alcohol exposure do not exhibit all features of fetal alcohol syndrome (FAS), and a challenge for clinicians is to make an early diagnosis of fetal alcohol spectrum disorders (FASD) to avoid lost opportunities for care. In brain, correct neurodevelopment requires proper angiogenesis. Since alcohol alters brain angiogenesis and the placenta is a major source of angiogenic factors, we hypothesized that it is involved in alcohol-induced brain vascular defects. In mouse, using in vivo repression and overexpression of PLGF, we investigated the contribution of placenta on fetal brain angiogenesis. In human, we performed a comparative molecular and morphological analysis of brain/placenta angiogenesis in alcohol-exposed fetuses. Results showed that prenatal alcohol exposure impairs placental angiogenesis, reduces PLGF levels and consequently alters fetal brain vasculature. Placental repression of PLGF altered brain VEGF-R1 expression and mimicked alcohol-induced vascular defects in the cortex. Over-expression of placental PGF rescued alcohol effects on fetal brain vessels. In human, alcohol exposure disrupted both placental and brain angiogenesis. PLGF expression was strongly decreased and angiogenesis defects observed in the fetal brain markedly correlated with placental vascular impairments. Placental PGF disruption impairs brain angiogenesis and likely predicts brain disabilities after in utero alcohol exposure. PLGF assay at birth could contribute to the early diagnosis of FASD.

Published
2017
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17. Hydrocephalus due to multiple ependymal malformations is caused by mutations in the MPDZ gene

Author

Pascale Saugier-Veber, Florent Marguet, François Lecoquierre, Homa Adle-Biassette, Fabien Guimiot, Sara Cipriani, Sophie Patrier, Marie Brasseur-Daudruy, Alice Goldenberg, Valérie Layet, Yline Capri, Marion Gérard, Thierry Frébourg, and Annie Laquerrière

Subjects
MPDZ pathogenic variants, Foetal hydrocephalus, Neuropathology, Multifocal malformation of the ependyma, Autosomal recessive inheritance, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Congenital hydrocephalus is considered as either acquired due to haemorrhage, infection or neoplasia or as of developmental nature and is divided into two subgroups, communicating and obstructive. Congenital hydrocephalus is either syndromic or non-syndromic, and in the latter no cause is found in more than half of the patients. In patients with isolated hydrocephalus, L1CAM mutations represent the most common aetiology. More recently, a founder mutation has also been reported in the MPDZ gene in foetuses presenting massive hydrocephalus, but the neuropathology remains unknown. We describe here three novel homozygous null mutations in the MPDZ gene in foetuses whose post-mortem examination has revealed a homogeneous phenotype characterized by multiple ependymal malformations along the aqueduct of Sylvius, the third and fourth ventricles as well as the central canal of the medulla, consisting in multifocal rosettes with immature cell accumulation in the vicinity of ependymal lining early detached from the ventricular zone. MPDZ also named MUPP1 is an essential component of tight junctions which are expressed from early brain development in the choroid plexuses and ependyma. Alterations in the formation of tight junctions within the ependyma very likely account for the lesions observed and highlight for the first time that primary multifocal ependymal malformations of the ventricular system is genetically determined in humans. Therefore, MPDZ sequencing should be performed when neuropathological examination reveals multifocal ependymal rosette formation within the aqueduct of Sylvius, of the third and fourth ventricles and of the central canal of the medulla.

Published
2017
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18. New Antibody-Free Mass Spectrometry-Based Quantification Reveals That C9ORF72 Long Protein Isoform Is Reduced in the Frontal Cortex of Hexanucleotide-Repeat Expansion Carriers

Author

Arthur Viodé, Clémence Fournier, Agnès Camuzat, François Fenaille, NeuroCEB Brain Bank, Morwena Latouche, Fanny Elahi, Isabelle Le Ber, Christophe Junot, Foudil Lamari, Vincent Anquetil, François Becher, Franck Letournel, Anne Vital, Françoise Chapon, Catherine Godfraind, Claude-Alain Maurage, Vincent Deramecourt, David Meyronnet, Nathalie Streichenberger, André Maues de Paula, Valérie Rigau, Fanny Vandenbos-Burel, Charles Duyckaerts, Danielle Seilhean, Véronique Sazdovitch, Serge Milin, Dan Christian Chiforeanu, Annie Laquerrière, and Béatrice Lannes

Subjects
frontotemporal dementia (FTD), frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), C9ORF72, TDP-43, TDP43, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Frontotemporal dementia (FTD) is a fatal neurodegenerative disease characterized by behavioral and language disorders. The main genetic cause of FTD is an intronic hexanucleotide repeat expansion (G4C2)n in the C9ORF72 gene. A loss of function of the C9ORF72 protein associated with the allele-specific reduction of C9ORF72 expression is postulated to contribute to the disease pathogenesis. To better understand the contribution of the loss of function to the disease mechanism, we need to determine precisely the level of reduction in C9ORF72 long and short isoforms in brain tissue from patients with C9ORF72 mutations. In this study, we developed a sensitive and robust mass spectrometry (MS) method for quantifying C9ORF72 isoform levels in human brain tissue without requiring antibody or affinity reagent. An optimized workflow based on surfactant-aided protein extraction and pellet digestion was established for optimal recovery of the two isoforms in brain samples. Signature peptides, common or specific to the isoforms, were targeted in brain extracts by multiplex MS through the parallel reaction monitoring mode on a Quadrupole–Orbitrap high resolution mass spectrometer. The assay was successfully validated and subsequently applied to frontal cortex brain samples from a cohort of FTD patients with C9ORF72 mutations and neurologically normal controls without mutations. We showed that the C9ORF72 short isoform in the frontal cortices is below detection threshold in all tested individuals and the C9ORF72 long isoform is significantly decreased in C9ORF72 mutation carriers.

Published
2018
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19. An Autopsy Case of Amyotrophic Lateral Sclerosis with Waldenström Macroglobulinemia and Anti-MAG Gammopathy

Author

Snejana Jurici, Annie Laquerrière, Anne-Laure Bedat-Millet, Fabrice Jardin, Lucile Musset, Jean-Michel Vallat, Didier Hannequin, and Olivier Martinaud

Subjects
Amyotrophic lateral sclerosis, Anti-MAG, Waldenström macroglobulinemia, Neurology. Diseases of the nervous system, RC346-429
Abstract

We report the case of a 71-year-old woman with typical signs of bulbar amyotrophic lateral sclerosis (ALS) associated with immunoglobulin M (IgM) monoclonal gammopathy and anti-MAG (myelin-associated glycoprotein) antibodies. This unusual association between ALS and anti-MAG antibodies has previously been reported in a single case. Our present case, at neuropathological examination, demonstrated no causative link between anti-MAG antibodies and ALS.

Published
2011
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20. 3-MA Inhibits Autophagy and Favors Long-Term Integration of Grafted Gad67–GFP GABAergic Precursors in the Developing Neocortex by Preventing Apoptosis

Author

Christian Roux, Céline Lesueur, Caroline Aligny, Carole Brasse-Lagnel, Damien Genty, Stéphane Marret, Annie Laquerrière, Soumeya Bekri, and Bruno J. Gonzalez

Subjects
Medicine
Abstract

In human neonates, immature GABAergic interneurons are markedly affected by an excitotoxic insult. While in adults the interest of cell transplantation has been demonstrated in several neurological disorders, few data are available regarding the immature brain. The low survival rate constitutes a strong limitation in the capacity of transplanted neurons to integrate the host tissue. Because i) autophagy is an adaptive process to energetic/nutrient deprivation essential for cell survival and ii) literature describes cross-talks between autophagy and apoptosis, we hypothesized that regulation of autophagy would represent an original strategy to favor long-term survival of GABAergic precursors grafted in the immature neocortex. Morphological, neurochemical, and functional data showed that in control conditions, few grafted Gad67-GFP precursors survived. The first hours following transplantation were a critical period with intense apoptosis. Experiments performed on E15.5 ganglionic eminences revealed that Gad67-GFP precursors were highly sensitive to autophagy. Rapamycin and 3-MA impacted on LC3 cleavage, LC3II translocation, and autophagosome formation. Quantification of Bax, mitochondrial integrity, caspase-3 cleavage, and caspase-3 immunolocalization and activity showed that 3-MA induced a significant decrease of Gad67-GFP precursor apoptosis. In vivo, 3-MA induced, within the first 24 h, a diffuse LC3 pattern of grafted Gad67-GFP precursors, an increase of precursors with neurites, a reduction of the density of caspase-3 immunoreactive cells. A twofold increase in the survival rate occurred 15 days after the graft. Surviving neurons were localized in the cortical layers II–IV, which were still immature when the transplantation was done. Altogether, these data indicate that inhibition of autophagy represents an original strategy to allow GABAergic interneurons to overpass the first critical hours following transplantation and to increase their long-term survival in mice neonates.

Published
2014
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21. Clinical and Molecular Characterization of Patients with Mucopolysaccharidosis Type I in an Algerian Series

Author

Abdellah Tebani, Lahouaria Zanoutene-Cheriet, Zoubir Adjtoutah, Lenaig Abily-Donval, Carole Brasse-Lagnel, Annie Laquerrière, Stephane Marret, Abla Chalabi Benabdellah, and Soumeya Bekri

Subjects
mucopolysaccharidosis type I, IDUA, GAGs, heparin sulfate, dermatan sulfate, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Mucopolysaccharidoses (MPS’s) represent a subgroup of lysosomal storage diseases related to a deficiency of enzymes that catalyze glycosaminoglycans degradation. Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder caused by a deficiency of α-l-iduronidase encoded by the IDUA gene. Partially degraded heparan sulfate and dermatan sulfate accumulate progressively and lead to multiorgan dysfunction and damage. The aim of this study is to describe the clinical, biochemical, and molecular characteristics of 13 Algerian patients from 11 distinct families. MPS I diagnosis was confirmed by molecular study of the patients’ IDUA gene. Clinical features at the diagnosis and during the follow-up are reported. Eighty-four percent of the studied patients presented with a mild clinical phenotype. Molecular study of the IDUA gene allowed the characterization of four pathological variations at the homozygous or compound heterozygote status: IDUA NM_00203.4:c.1598C>G-p.(Pro533Arg) in 21/26 alleles, IDUA NM_00203.4:c.532G>A-p.(Glu178Lys) in 2/26 alleles, IDUA NM_00203.4:c.501C>G-p.(Tyr167*) in 2/26 alleles, and IDUA NM_00203. 4: c.1743C>G-p.(Tyr581*) in 1/26 alleles. This molecular study unveils the predominance of p.(Pro533Arg) variation in our MPS I patients. In this series, the occurrence of some clinical features linked to the Scheie syndrome is consistent with the literature, such as systematic valvulopathies, corneal opacity, and umbilical hernia; however, storage signs, facial dysmorphic features, and hepatomegaly were more frequent in our series. Screening measures for these debilitating diseases in highly consanguineous at-risk populations must be considered a priority health problem.

Published
2016
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22. Recessive PRDM13 mutations cause fatal perinatal brainstem dysfunction with cerebellar hypoplasia and disrupt Purkinje cells differentiation

Author

Marion Coolen, Nami Altin, Karthyayani Rajamani, Eva Pereira, Karine Siquier-Pernet, Emilia Puig Lombardi, Nadjeda Moreno, Giulia Barcia, Marianne Yvert, Annie Laquerrière, Aurore Pouliet, Patrick Nitschké, Nathalie Boddaert, Antonio Rausell, Féréchté Razavi, Alexandra Afenjar, Thierry Billette de Villemeur, Almundher Al-Maawali, Khalid Al-Thihli, Julia Baptista, Ana Beleza-Meireles, Catherine Garel, Marine Legendre, Antoinette Gelot, Lydie Burglen, Sébastien Moutton, Vincent Cantagrel, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Great Ormond Street Institute of Child Health (UCL), University College of London [London] (UCL), Maison de Santé Protestante de Bordeaux-Bagatelle (MSPB), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), URC, hôpital Necker Enfants Maladies, Paris, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Sultan Qaboos University (SQU), Peninsula Medical School, University Hospitals Bristol, Hôpital des Enfants - Groupe hospitalier Pellegrin - CHU de Bordeaux, Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ANR-16-CE12-0005,SCD-Mec,Mécanismes développementaux des anomalies structurelles cérébelleuses(2016)

Subjects
Brain Diseases, Developmental Disabilities, Neurogenesis, Histone-Lysine N-Methyltransferase, Nervous System Malformations, Article, Mice, Purkinje Cells, Cerebellum, Mutation, Genetics, Animals, Humans, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Genetics (clinical), Zebrafish, ComputingMilieux_MISCELLANEOUS, Brain Stem, Transcription Factors
Abstract

Pontocerebellar hypoplasias (PCHs) are congenital disorders characterized by hypoplasia or early atrophy of the cerebellum and brainstem, leading to a very limited motor and cognitive development. Although over 20 genes have been shown to be mutated in PCHs, a large proportion of affected individuals remains undiagnosed. We describe four families with children presenting with severe neonatal brainstem dysfunction and pronounced deficits in cognitive and motor development associated with four different bi-allelic mutations in PRDM13, including homozygous truncating variants in the most severely affected individuals. Brain MRI and fetopathological examination revealed a PCH-like phenotype, associated with major hypoplasia of inferior olive nuclei and dysplasia of the dentate nucleus. Notably, histopathological examinations highlighted a sparse and disorganized Purkinje cell layer in the cerebellum. PRDM13 encodes a transcriptional repressor known to be critical for neuronal subtypes specification in the mouse retina and spinal cord but had not been implicated, so far, in hindbrain development. snRNA-seq data mining and in situ hybridization in humans show that PRDM13 is expressed at early stages in the progenitors of the cerebellar ventricular zone, which gives rise to cerebellar GABAergic neurons, including Purkinje cells. We also show that loss of function of prdm13 in zebrafish leads to a reduction in Purkinje cells numbers and a complete absence of the inferior olive nuclei. Altogether our data identified bi-allelic mutations in PRDM13 as causing a olivopontocerebellar hypoplasia syndrome and suggest that early deregulations of the transcriptional control of neuronal fate specification could contribute to a significant number of cases.

Published
2022

23. Cell-free DNA and circulating TERT promoter mutation for disease monitoring in newly-diagnosed glioblastoma

Author

Ludivine Beaussire, Louis-Ferdinand Pepin, Maxime Fontanilles, Florent Marguet, Frédéric Di Fiore, Olivier Langlois, Fabrice Jardin, Nicolas Magne, Annie Laquerrière, Florian Clatot, Cristina Alexandru, Chantal Hanzen, Isabelle Tennevet, and Nasrin Sarafan-Vasseur

Subjects
Male, Oncology, medicine.medical_specialty, Gliosarcoma, medicine.medical_treatment, Neurosurgical Procedures, lcsh:RC346-429, Pathology and Forensic Medicine, Cellular and Molecular Neuroscience, Cell-free DNA, Internal medicine, Temozolomide, Humans, Medicine, Liquid biopsy, TERT promoter mutation, Promoter Regions, Genetic, Prospective cohort study, Antineoplastic Agents, Alkylating, Telomerase, lcsh:Neurology. Diseases of the nervous system, Aged, Circulating tumor DNA, Brain Neoplasms, business.industry, Research, Chemoradiotherapy, Middle Aged, medicine.disease, Radiation therapy, Cell-free fetal DNA, Concomitant, Mutation, Female, Neurology (clinical), business, Glioblastoma, Cell-Free Nucleic Acids, Progressive disease, medicine.drug
Abstract

The clinical implications of plasmatic cell-free and tumor DNA (cfDNA and ctDNA) are challenging in glioblastoma. This prospective study included 52 consecutive newly diagnosed glioblastoma (n = 49) or gliosarcoma (n = 3) patients treated with concomitant temozolomide and radiotherapy (RT-TMZ), followed by a TMZ maintenance phase. Plasma samples were collected at baseline, before RT-TMZ (pre-RT-TMZ) and at the end of adjuvant TMZ, or at the time of progression in cases of progressive disease (PD). The cfDNA concentration was measured with a fluorometric method, and ctDNA was detected using targeted droplet digital PCR. The main objectives were to analyze the associations between cfDNA and ctDNA measurements during the course of treatment with PD and survival. There was a significant decrease in median cfDNA concentration from baseline to pre-RT-TMZ—19.4 versus 9.7 ng/mL (p p = 0.037), respectively, while no difference was observed for nonprogressive patients. Neither the cfDNA concentration at baseline nor its kinetics correlated with survival. ctDNA was detected in 2 patients (3.8%) and only in gliosarcoma subtypes.Trial registration ClinicalTrial, NCT02617745. Registered 1 December 2015, https://clinicaltrials.gov/ct2/show/NCT02617745?term=glioplak&draw=2&rank=1.

Published
2020

24. Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenital

Author

Ivo Gut, Sarah Grotto, Céline Bellesme, Arnold Munnich, Cyril Gitiaux, Jeanne Amiel, Chloé Quélin, Annie Laquerrière, Suonavy Khung, Hanitra Ranjatoelina-Randrianaivo, Luc Rigonnot, Christine Francannet, Loic Quevarec, Jérôme Bouligand, Fabienne Prieur, Alexandra Benachi, Valérie Cormier-Daire, Laurence Perrin, Judith Melki, Pierre-Simon Jouk, Flora Nolent, Tania Attié-Bitach, Delphine Héron, Marie-Line Jacquemont, Claire Beneteau, Fabien Guimiot, Laetitia Lambert, Sandra Mercier, Valérie Biancalana, Fanny Laffargue, Elise Boucher, Jean-Louis Bessereau, P. Landrieu, Annick Toutain, Alain Verloes, Alice Goldenberg, Philippe Latour, Dominique Martin-Coignard, Anne Guiochon-Mantel, Dan Mejlachowicz, Damien Sternberg, Haluk Topaloglu, Bruno Eymard, Géraldine Viot, Catherine Fallet-Bianco, Julien Saada, Isabelle Desguerre, Marie-Hélène Saint-Frison, Catherine Vincent-Delorme, Sophie Blesson, Radka Stoeva, Alexandre J. Vivanti, Martine Bucourt, Pascaline Letard, Jérome Maluenda, Laurence Loeuillet, Lionel Van Maldergem, Didier Lacombe, Marcel Tawk, Michèle Granier, Stanislas Lyonnet, Anne-Lise Delezoide, Andrée Delahaye-Duriez, André Mégarbané, Marie Gonzales, Florence Petit, Juliette Piard, Laurence Faivre, Helene Verhelst, Bettina Bessières, Sabine Sigaudy, Sandra Whalen, Valérie Layet, Yline Capri, Fanny Pelluard, Emanuela Abiusi, Klaus Dieterich, Marie Vincent, Marine Legendre, Dana Jaber, Romulus Grigorescu, Florent Marguet, Eric Bieth, Helge Amthor, Christine Barnerias, Estelle Colin, Laetitia Trestard, Mathilde Nizon, Jelena Martinovic, Daniel Amram, and Nicoletta Resta

Subjects
musculoskeletal diseases, Artrogriposi múltiple congènita, Settore BIO/18 - GENETICA, human genetics, neuromuscular diseases, Genomics, Biology, CONTRACTURES, CLASSIFICATION, diseases, symbols.namesake, Diagnòstic, Gene mapping, arthrogryposis multiplex congenita, Exome Sequencing, OF-FUNCTION MUTATIONS, Genetics, Medicine and Health Sciences, genomics, Humans, Genetics (clinical), Exome sequencing, Arthrogryposis, Sanger sequencing, Arthrogryposis multiplex congenita, Genetic heterogeneity, SPINAL MUSCULAR-ATROPHY, Proteins, nervous system malformations, DYSTROPHY, Disease gene identification, GENE, Human genetics, Pedigree, ETIOLOGY, Phenotype, symbols, neuromuscular, Genètica, Transcription Factors
Abstract

BackgroundArthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families.MethodsSeveral genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants.ResultsWe achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (CNTNAP1, MAGEL2, ADGRG6, ADCY6, GLDN, LGI4, LMOD3, UNC50 and SCN1A). Moreover, we identified pathogenic variants in ASXL3 and STAC3 expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%).ConclusionNew genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.

Published
2022

25. Neuropathological hallmarks of fetal hydrocephalus linked to CCDC88C pathogenic variants

Author

Myriam Vezain, Bruno J. Gonzalez, Florent Marguet, Annie Laquerrière, Nathalie Drouot, Arie Horowitz, Pascale Saugier-Veber, Kévin Cassinari, Pascale Marcorelles, Séverine Audebert-Bellanger, and Pascal Chambon

Subjects
Adult, Pathology, medicine.medical_specialty, Choroid plexus hydrops, Case Report, Neuropathology, Diaphragmatic defect, Biology, Pathology and Forensic Medicine, Cellular and Molecular Neuroscience, Fetus, Multiple ependymal malformations, Pregnancy, Foetal hydrocephalus, medicine, Humans, RC346-429, CCDC88C pathogenic variants, Neural tube defect, Microfilament Proteins, Wnt signaling pathway, Neural tube, Intracellular Signaling Peptides and Proteins, Brain, medicine.disease, Planar cell polarity, Autosomal recessive inheritance, Hydrocephalus, Pedigree, Bilateral Renal Agenesis, Fetal Diseases, medicine.anatomical_structure, Renal agenesis, Mutation, Choroid plexus, Female, Neurology. Diseases of the nervous system, Neurology (clinical), Ventriculomegaly
Abstract

The prevalence of congenital hydrocephalus has been estimated at 1.1 per 1000 infants when including cases diagnosed before 1 year of age after exclusion of neural tube defects. Classification criteria are based either on CSF dynamics, pathophysiological mechanisms or associated lesions. Whereas inherited syndromic hydrocephalus has been associated with more than 100 disease-causing genes, only four genes are currently known to be linked to congenital hydrocephalus either isolated or as a major clinical feature: L1CAM, AP1S2, MPDZ and CCDC88C. In the past 10 years, pathogenic variants in CCDC88C have been documented but the neuropathology remains virtually unknown. We report the neuropathology of two foetuses from one family harbouring two novel compound heterozygous pathogenic variants in the CCDC88C gene: a maternally inherited indel in exon 22, c.3807_3809delinsACCT;p.(Gly1270Profs*53) and a paternally inherited deletion of exon 23, c.3967-?_c.4112-?;p.(Leu1323Argfs*10). Medical termination of pregnancy was performed at 18 and 23 weeks of gestation for severe bilateral ventriculomegaly. In both fetuses, brain lesions consisted of multifocal atresia-forking along the aqueduct of Sylvius and the central canal of the medulla, periventricular neuronal heterotopias and choroid plexus hydrops. The second fetus also presented lumbar myelomeningocele, left diaphragmatic hernia and bilateral renal agenesis. CCDC88C encodes the protein DAPLE which contributes to ependymal cell planar polarity by inhibiting the non-canonical Wnt signaling pathway and interacts with MPDZ and PARD3. Interestingly, heterozygous variants in PARD3 result in neural tube defects by defective tight junction formation and polarization process of the neuroepithelium. Besides, during organ formation Wnt signalling is a prerequisite for planar cell polarity pathway activation, and mutations in planar cell polarity genes lead to heart, lung and kidney malformations. Hence, candidate variants in CCDC88C should be carefully considered whether brain lesions are isolated or associated with malformations suspected to result from disorders of planar cell polarity.

Published
2021

26. Simultaneous detection of EGFR amplification and EGFRvIII variant using digital PCR-based method in glioblastoma

Author

Philippe Ruminy, Annie Laquerrière, Adrien Noel, Cristina Alexandru, Pierre-Julien Viailly, Pascal Chambon, Doriane Richard, Maxime Fontanilles, Kévin Cassinari, Frédéric Di Fiore, Isabelle Tennevet, Florent Marguet, Mathieu Viennot, Ludivine Beaussire, Carole Basset, Olivier Langlois, Florian Clatot, and Nasrin Sarafan-Vasseur

Subjects
Adult, Male, Cost effectiveness, Polymerase Chain Reaction, lcsh:RC346-429, Pathology and Forensic Medicine, Cellular and Molecular Neuroscience, Exon, medicine, Temozolomide, Humans, Digital polymerase chain reaction, EGFR amplification, Epidermal growth factor receptor, Locked nucleic acid, lcsh:Neurology. Diseases of the nervous system, Aged, EGFRvIII variant, medicine.diagnostic_test, biology, Brain Neoplasms, Methodology Article, Intron, Gene Amplification, Chemoradiotherapy, Amplicon, Middle Aged, Molecular biology, ErbB Receptors, biology.protein, Cost-effectiveness, Female, Neurology (clinical), Glioblastoma, Digital PCR, Biomarkers, Fluorescence in situ hybridization
Abstract

Epidermal growth factor receptor (EGFR) amplification and EGFR variant III (EGFRvIII, deletion of exons 2–7) are of clinical interest for glioblastoma. The aim was to develop a digital PCR (dPCR)-based method using locked nucleic acid (LNA)-based hydrolysis probes, allowing the simultaneous detection of the EGFR amplification and EGFRvIII variant. Sixty-two patients were included. An exploratory cohort (n = 19) was used to develop the dPCR assay using three selected amplicons within the EGFR gene, targeting intron 1 (EGFR1), junction of exon 3 and intron 3 (EGFR2) and intron 22 (EGFR3). The copy number of EGFR was estimated by the relative quantification of EGFR1, EGFR2 and EGFR3 amplicon droplets compared to the droplets of a reference gene. EGFRvIII was identified by comparing the copy number of the EGFR2 amplicon to either the EGFR1 or EGFR3 amplicon. dPCR results were compared to fluorescence in situ hybridization (FISH) and next-generation sequencing for amplification; and to RT-PCR-based method for EGFRvIII. The dPCR assay was then tested in a validation cohort (n = 43). A total of 8/19 EGFR-amplified and 5/19 EGFRvIII-positive tumors were identified in the exploratory cohort. Compared to FISH, the EGFR3 dPCR assay detected all EGFR-amplified tumors (8/8, 100%) and had the highest concordance with the copy number estimation by NGS. The concordance between RT-PCR and dPCR was also 100% for detecting EGFRvIII using an absolute difference of 10.8 for the copy number between EGFR2 and EGFR3 probes. In the validation cohort, the sensitivity and specificity of dPCR using EGFR3 probes were 100% for the EGFR amplification detection compared to FISH (19/19). EGFRvIII was detected by dPCR in 8 EGFR-amplified patients and confirmed by RT-PCR. Compared to FISH, the EGFR2/EGFR3 dPCR assay was estimated with a one-half cost value. These results highlight that dPCR allowed the simultaneous detection of EGFR amplification and EGFRvIII for glioblastoma.

Published
2020

27. Pontocerebellar hypoplasia with rhombencephalosynapsis and microlissencephaly expands the spectrum of PCH type 1B

Author

Annie Laquerrière, Pascale Saugier-Veber, Martine Bucourt, Andrée Delahaye, Florent Marguet, Thierry Frebourg, Pascaline Letard, Myriam Vezain, Bruno J. Gonzalez, Eva Pipiras, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Team 4 'NeoVasc' - INSERM U1245, Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Service Histologie-embryologie-cytogénétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [AP-HP], and Service d'Anatomie et Cytologie Pathologique [CHU Rouen]

Subjects
0301 basic medicine, education.field_of_study, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Population, Pontocerebellar hypoplasia, General Medicine, Spinal muscular atrophy, 030105 genetics & heredity, Biology, medicine.disease, Hypoplasia, 03 medical and health sciences, 030104 developmental biology, Atrophy, Agenesis, Genetics, medicine, Cerebellar atrophy, Global developmental delay, 10. No inequality, education, Genetics (clinical), ComputingMilieux_MISCELLANEOUS
Abstract

Rhombencephalosynapsis is a rare cerebellar malformation developing during embryogenesis defined by vermian agenesis or hypogenesis with fusion of the cerebellar hemispheres. It occurs either alone or in association with other cerebral and/or extracerebral anomalies. Its association with microlissencephaly is exceedingly rare and to date, only a heterozygous de novo missense variant in ADGRL2, a gene encoding Adhesion G-Protein-Coupled Receptor L2, has been identified. We report on two siblings of Roma origin presenting with severe growth retardation, fetal akinesia, microlissencephaly and small cerebellum with vermian agenesis. Neuropathological studies revealed extreme paucity in pontine transverse fibres, rudimentary olivary nuclei and rhombencephalosynapsis with vanishing spinal motoneurons in both fetuses. Comparative fetus-parent exome sequencing revealed in both fetuses a homozygous variant in exon 1 of the EXOSC3 gene encoding a core component of the RNA exosome, c.92G > C; p.(Gly31Ala). EXOSC3 accounts for 40%–75% of patients affected by ponto-cerebellar hypoplasia with spinal muscular atrophy (PCH1B). The c.92G > C variant is a founder mutation in the Roma population and has been reported in severe PCH1B. PCH1B is characterized by a broad phenotypic spectrum, ranging from mild phenotypes with spasticity, mild to moderate intellectual disability, pronounced distal muscular and cerebellar atrophy/hypoplasia, to severe phenotypes with profound global developmental delay, progressive microcephaly and atrophy of the cerebellar hemispheres. In PCH1B, the usual cerebellar lesions affect mainly the hemispheres with relative sparing of vermis that radically differs from rhombencephalosynapsis. This unusual foetal presentation expands the spectrum of PCH1B and highlights the diversity of rhombencephalosynapsis etiologies.

Published
2019

28. Fetal alcohol exposure: when placenta would help to the early diagnosis of child brain impairments

Author

Matthieu Jean Alexandre Lecuyer, Soumeya Bekri, Sylvie Jégou, Pascale Marcorelles, Bruno J. Gonzalez, Stéphane Marret, Annie Laquerrière, Camille Sautreuil, Sophie Gil, Carole Brasse-Lagnel, Team 4 'NeoVasc' - INSERM U1245, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratoire de biochimie générale [Rouen], Normandie Université (NU)-Centre hospitalier universitaire de Rouen, Service d'Anatomie Pathologique, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Physiopathologie et pharmacotoxicologie placentaire humaine : Microbiote pré & post natal (3PHM - UMR-S 1139), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)

Subjects
0303 health sciences, Pregnancy, business.industry, [SDV]Life Sciences [q-bio], Fetal alcohol syndrome, General Medicine, Alcohol exposure, medicine.disease, Bioinformatics, General Biochemistry, Genetics and Molecular Biology, Alcohol consumption during pregnancy, 03 medical and health sciences, Fetal alcohol, 0302 clinical medicine, medicine.anatomical_structure, In utero, Fetal Alcohol Spectrum Disorder, Placenta, medicine, business, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

La consommation d’alcool au cours de la grossesse constitue une cause majeure de troubles du comportement et de handicap. Alors qu’il est possible pour un clinicien d’établir un diagnostic néonatal du syndrome d’alcoolisation fœtale, l’atteinte la plus sévère des troubles causés par l’alcoolisation fœtale (TCAF), une grande majorité des enfants échappe à un diagnostic précoce en raison de l’absence d’anomalies morphologiques évidentes. Plusieurs années de prise en charge sont alors perdues. Des avancées récentes ont permis d’établir l’existence d’un axe fonctionnel placenta-cerveau impliqué dans le contrôle de l’angiogenèse cérébrale, qui se trouve dérégulé chez les enfants exposés in utero à l’alcool. Une angiogenèse cérébrale normale étant un prérequis à l’établissement d’un neurodéveloppement correct, ces avancées ouvrent la voie à l’identification d’une nouvelle génération de biomarqueurs placentaires d’atteinte cérébrale pour le diagnostic précoce des enfants TCAF.

Published
2019

29. TERTp Mutation Detection in Plasma by Droplet-Digital Polymerase Chain Reaction in Spinal Myxopapillary Ependymoma with Lung Metastases

Author

Frédéric Di Fiore, Ludivine Beaussire, Marco-Achille Gambirasio, Annie Laquerrière, Ovidiu Veresezan, M. Fontanilles, Christophe Peillon, Nasrin Sarafan-Vasseur, Florent Marguet, Nicolas Magne, Anne-Claire Tobenas-Dujardin, Anne Deniel, Department of Pathology, Rouen University Hospital, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de chirurgie cadiovasculaire et thoracique [Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service de Radiologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Département d'oncologie médicale [Rouen], Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement (Néovasc), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-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), and Génétique du cancer et des maladies neuropsychiatriques (GMFC)

Subjects
Adult, Pathology, medicine.medical_specialty, Lung Neoplasms, [SDV]Life Sciences [q-bio], Extraneural, medicine.disease_cause, Polymerase Chain Reaction, Metastasis, 03 medical and health sciences, 0302 clinical medicine, medicine, Biomarkers, Tumor, Humans, Digital polymerase chain reaction, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Spinal Cord Neoplasms, Liquid biopsy, Promoter Regions, Genetic, Allele frequency, Telomerase, ComputingMilieux_MISCELLANEOUS, Mutation, business.industry, DNA, Neoplasm, medicine.disease, Reverse transcriptase, 3. Good health, Anaplastic Lesion, Ependymoma, 030220 oncology & carcinogenesis, Surgery, Female, Neurology (clinical), business, Cell-Free Nucleic Acids, 030217 neurology & neurosurgery
Abstract

Background Spinal myxopapillary ependymoma (SP-MPE) is a subgroup of ependymomas in which after initial gross tumor resection, recurrences occur in more than half of the patients. Anaplastic transformation may also occur and contributes to intraneural and extraneural metastatic dissemination. Extraneural metastases from SP-MPE are rare and worsen the prognosis. In this situation, the noninvasive detection of recurrent somatic mutations in the circulating tumor DNA (ctDNA) from plasma is challenging. Telomerase-reverse transcriptase gene promoter (TERTp) mutation has been identified in a subset of ependymomas with aggressive behavior. Case Description We report on a patient with TERTp mutated SP-MPE presenting with an extraneural anaplastic metastatic dissemination after iterative local recurrences. From the initial SP-MPE to pleural anaplastic lesion, TERTp C228T mutation was present with allele frequency varying from 33% to 39%. Interestingly, TERTp mutation was also detected by droplet digital polymerase chain reaction in the plasma with a frequency of 2.1% at the time of pleural metastases, highlighting that ctDNA is released in plasma of patients suffering from SP-MPE with extraneural metastatic dissemination. Conclusions Despite the rarity of this evolution, plasmatic liquid biopsy appears to be a useful diagnostic and follow-up tool in a subset of primary brain tumors.

Published
2019

30. Copy Number Variants in miR-138 as a Potential Risk Factor for Early-Onset Alzheimer’s Disease

Author

Anne Boland, Gaël Nicolas, Camille Charbonnier, Sébastien S. Hébert, Annie Laquerrière, Kévin Cassinari, Emmanuelle Boscher, Dominique Campion, Olivier Martinaud, Jean-François Deleuze, Thomas Husson, David Wallon, Olivier Quenez, Mark Lathrop, Anne Rovelet-Lecrux, Florent Marguet, Thierry Frebourg, CHU de Québec–Université Laval, Université Laval [Québec] (ULaval), Faculté de médecine de l'Université Laval [Québec] (ULaval), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), Department of Pathology, Rouen University Hospital, Service de neurologie [Rouen], CHU Rouen, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Research, Centre hospitalier du Rouvray, Sotteville-lès-Rouen, France, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), and Département de Pathologie [CHU Rouen]

Subjects
Adult, Male, 0301 basic medicine, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Blotting, Western, miR-138, Locus (genetics), Biology, Real-Time Polymerase Chain Reaction, Gene dosage, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Risk Factors, Exome Sequencing, PSEN2, Gene duplication, mental disorders, PSEN1, medicine, Humans, Genetic Predisposition to Disease, Early-onset Alzheimer's disease, Copy-number variation, Age of Onset, Cells, Cultured, Exome sequencing, Aged, Genetics, Copy number variants, microRNA, General Neuroscience, early-onset Alzheimer’s disease, General Medicine, Middle Aged, medicine.disease, 3. Good health, MicroRNAs, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, Case-Control Studies, Female, Geriatrics and Gerontology, Multiplex Polymerase Chain Reaction, 030217 neurology & neurosurgery
Abstract

International audience; Early-onset Alzheimer’s disease (EOAD) accounts for 5-10% of all AD cases, with a heritability ranging between 92% to 100%. With the exception of rare mutations in APP, PSEN1, and PSEN2 genes causing autosomal dominant EOAD, little is known about the genetic factors underlying most of the EOAD cases. In this study, we hypothesized that copy number variations (CNVs) in microRNA (miR) genes could contribute to risk for EOAD. miRs are short non-coding RNAs previously implicated in the regulation of AD-related genes and phenotypes. Using whole exome sequencing, we screened a series of 546 EOAD patients negative for autosomal dominant EOAD mutations and 597 controls. We identified 86 CNVs in miR genes of which 31 were exclusive to EOAD cases, including a duplication of the MIR138-2 locus. In functional studies in human cultured cells, we could demonstrate that miR-138 overexpression leads to higher Aβ production as well as tau phosphorylation, both implicated in AD pathophysiology. These changes were mediated in part by GSK-3β and FERMT2, a potential risk factor for AD. Additional disease-related genes were also prone to miR-138 regulation including APP and BACE1. This study suggests that increased gene dosage of MIR138-2 could contribute to risk for EOAD by regulating different biological pathways implicated in amyloid and tau metabolism. Additional studies are now required to better understand the role of miR-CNVs in EOAD.

Published
2019

31. Phenotype and imaging features associated with APP duplications

Author

Lou Grangeon, Camille Charbonnier, Aline Zarea, Stephane Rousseau, Anne Rovelet-Lecrux, David Bendetowicz, Marion Lemaitre, Cécile Malrain, Muriel Quillard-Muraine, Kevin Cassinari, David Maltete, Jeremie Pariente, Olivier Moreaud, Eloi Magnin, Benjamin Cretin, Marie-Anne Mackowiak, Adeline Rollin Sillaire, Martine Vercelletto, Elsa Dionet, Olivier Felician, Pauline Rod-Olivieri, Catherine Thomas-Antérion, Gaelle Godeneche, Mathilde Sauvée, Leslie Cartz-Piver, Isabelle Le Ber, Valérie Chauvire, Therèse Jonveaux, Anna-Chloé Balageas, Annie Laquerriere, Charles Duyckaerts, Anne Vital, Andre Maues de Paula, David Meyronet, Lucie Guyant-Marechal, Didier Hannequin, Elisabeth Tournier-Lasserve, Dominique Campion, CNR-MAJ collaborators, Gaël Nicolas, and David Wallon

Subjects
Cerebral amyloid angiopathy, Alzheimer disease, APP duplication, Cerebral MRI, Autosomal dominant, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background APP duplication is a rare genetic cause of Alzheimer disease and cerebral amyloid angiopathy (CAA). We aimed to evaluate the phenotypes of APP duplications carriers. Methods Clinical, radiological, and neuropathological features of 43 APP duplication carriers from 24 French families were retrospectively analyzed, and MRI features and cerebrospinal fluid (CSF) biomarkers were compared to 40 APP-negative CAA controls. Results Major neurocognitive disorders were found in 90.2% symptomatic APP duplication carriers, with prominent behavioral impairment in 9.7%. Symptomatic intracerebral hemorrhages were reported in 29.2% and seizures in 51.2%. CSF Aβ42 levels were abnormal in 18/19 patients and 14/19 patients fulfilled MRI radiological criteria for CAA, while only 5 displayed no hemorrhagic features. We found no correlation between CAA radiological signs and duplication size. Compared to CAA controls, APP duplication carriers showed less disseminated cortical superficial siderosis (0% vs 37.5%, p = 0.004 adjusted for the delay between symptoms onset and MRI). Deep microbleeds were found in two APP duplication carriers. In addition to neurofibrillary tangles and senile plaques, CAA was diffuse and severe with thickening of leptomeningeal vessels in all 9 autopsies. Lewy bodies were found in substantia nigra, locus coeruleus, and cortical structures of 2/9 patients, and one presented vascular amyloid deposits in basal ganglia. Discussion Phenotypes associated with APP duplications were heterogeneous with different clinical presentations including dementia, hemorrhage, and seizure and different radiological presentations, even within families. No apparent correlation with duplication size was found. Amyloid burden was severe and widely extended to cerebral vessels as suggested by hemorrhagic features on MRI and neuropathological data, making APP duplication an interesting model of CAA.

Published
2023
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32. Somatic variants in autosomal dominant genes are a rare cause of sporadic Alzheimer's disease

Author

Dominique Campion, Colin Smith, Manon S. Oud, Safa Al Sarraj, Stefan H. Lelieveld, Gaël Nicolas, Anne-Claire Richard, Florent Marguet, Christian Gilissen, Thierry Frebourg, Alexander Hoischen, Joris A. Veltman, Rocio Acuna-Hidalgo, Didier Hannequin, Stéphane Rousseau, Patrick F. Chinnery, Olivier Quenez, Olaf Ansorge, Christopher Morris, Annie Laquerrière, Michael J. Keogh, Johannes Attems, David Wallon, Marloes Steehouwer, Chinnery, Patrick [0000-0002-7065-6617], Apollo - University of Cambridge Repository, PORCHET, Nathalie, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Radboud University Medical Center [Nijmegen], Department of Clinical Neurosciences [Cambridge], University of Cambridge [UK] (CAM), Department of Human Genetics [Nijmegen], Département de Pathologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Institute of Neuroscience [Newcastle] (ION), Newcastle University [Newcastle], Building Research Establishment (BRE/Edinburgh), University of Edinburgh, John Radcliffe Hospital [Oxford University Hospital], King‘s College London, Department of Research, Centre hospitalier du Rouvray, Sotteville-lès-Rouen, France, Service de neurologie [Rouen], Mitochondrial Research Group, University of Northumbria at Newcastle [United Kingdom], and Department of Pathology, Rouen University Hospital

Subjects
0301 basic medicine, Post‐zygotic, Adult, Male, Epidemiology, Somatic cell, [SDV]Life Sciences [q-bio], SORL1, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Biology, medicine.disease_cause, Deep sequencing, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, Developmental Neuroscience, Alzheimer Disease, PSEN2, medicine, PSEN1, Humans, Genetic Predisposition to Disease, Prion‐like, Allele, Prion-like, Aged, Genes, Dominant, Genetics, Mutation, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Mosaicism, Post-zygotic, Health Policy, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Amplicon, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Psychiatry and Mental health, 030104 developmental biology, Alzheimer, Female, Neurology (clinical), Geriatrics and Gerontology, 030217 neurology & neurosurgery
Abstract

Introduction A minority of patients with sporadic early-onset Alzheimer's disease (AD) exhibit de novo germ line mutations in the autosomal dominant genes such as APP , PSEN1 , or PSEN2 . We hypothesized that negatively screened patients may harbor somatic variants in these genes. Methods We applied an ultrasensitive approach based on single-molecule molecular inversion probes followed by deep next generation sequencing of 11 genes to 100 brain and 355 blood samples from 445 sporadic patients with AD (>80% exhibited an early onset, Results We identified and confirmed nine somatic variants (allele fractions: 0.2%–10.8%): two APP , five SORL1 , one NCSTN , and one MARK4 variant by independent amplicon-based deep sequencing. Discussion Two of the SORL1 variant might have contributed to the disease, the two APP variants were interpreted as likely benign and the other variants remained of unknown significance. Somatic variants in the autosomal dominant AD genes may not be a common cause of sporadic AD, including early onset cases.

Published
2018

33. EMBR-17. PINEOBLASTOMA SEGREGATES INTO MOLECULAR SUBTYPES WITH DISTINCT CLINICOPATHOLOGIC FEATURES: REPORT FROM THE RARE BRAIN TUMOR CONSORTIUM

Author

Anne Jouvet, Xing Fan, Annie Laquerrière, Guillaume Gauchotte, Richard Grundy, Eugene Hwang, Jason Fangusaro, Michael D. Taylor, Gino R. Somers, Maryam Fouladi, Alexandre Vasiljevic, Fabien Forest, Christelle Dufour, Helen Toledano, Karima Mokhtari, Amar Gajjar, David S. Ziegler, Scott L. Pomeroy, Ben Ho, Marie-Bernadette Delisle, Eric Bouffet, Jordan R. Hansford, Lindsey M. Hoffman, Mei Lu, Sridharan Gururangan, Audrey Rousseau, Delphine Loussouarn, Bryan K. Li, Diane K. Birks, Cynthia Hawkins, Nobusawa Sumihito, Chris Jones, Annie Huang, and Joseph D. Norman

Subjects
Pineoblastoma, Cancer Research, Pathology, medicine.medical_specialty, business.industry, Brain tumor, Methylation, Brain tumor childhood, medicine.disease, Painful Bladder Syndrome, Abstracts, Oncology, medicine, Neurology (clinical), business
Abstract

Pineoblastoma (PB) is a rare but aggressive pediatric brain tumour arising from the pineal gland. Outcomes remain dismal with long-term survival rates between 10–40% despite intensive treatment regimens. Although germline RB1 and DICER1 alterations have been reported in a small proportion of PB, the clinical significance of such alterations and the biology of sporadic cases remains unknown. We undertook global methylation profiling of 75 PB cases, and discovered that PBs comprise four molecular sub-types, designated groups 1 to 4 with characteristic copy number alterations and mutational patterns. Molecular sub-groups of PB also exhibited distinct clinical features and survival outcomes. While PBs group 1–3 arose in older children (median ages 5.2–12.6 years), group 4 PB was restricted to much younger children (median age 1.4 years). Group 4 PB exhibited the highest incidence of metastases (53%) and had the worst 5-year event-free survival (EFS) and overall survival (OS), respectively 7.7% and 16.7%. In contrast, group 2 patients had a 5-year EFS and OS of 100%, while group 1 and 3 had intermediate outcomes (68.1%, 53.3% respectively). These findings demonstrate significant clinical and molecular heterogeneity in PB and underscore the critical need to define mechanisms underlying PB, so that precise patient stratification and selection of biology-informed therapies can be undertaken in future clinical trials.

Published
2018

34. Patterns and severity of vascular amyloid in Alzheimer’s disease associated with duplications and missense mutations in APP gene, Down syndrome and sporadic Alzheimer’s disease

Author

Anna Richardson, Nancy Allen, Matthew Jones, David M. A. Mann, Takeshi Iwatsubo, Annie Laquerrière, Julie S. Snowden, Neil Pendleton, Marie-Claude Potier, Andre Strydom, Andrew C Robinson, Yvonne S Davidson, Vee P. Prasher, Tadafumi Hashimoto, Division of Neuroscience and Experimental Psychology [Salford, UK], University of Manchester [Manchester]-Salford Royal NHS Foundation Trust [Salford, UK], Department of Neuropathology [Tokyo, Japan], The University of Tokyo (UTokyo), Cerebral Function Unit [Salford, UK] (Greater Manchester Neurosciences Centre), Salford Royal Hospital [Salford, UK], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Centre National de la Recherche Scientifique (CNRS), Team 4 NeoVasc - Region Team ERI 28 INSERM (Neovasc), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Pathologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Birmingham Community NHS Trust [Birmingham, UK], Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, Division of Psychiatry [London, UK], University College of London [London] (UCL), We acknowledge the support of the Manchester Brain Bank by Alzheimer’s Research UK and Alzheimer’s Society through their funding of the Brains for Dementia Research (BDR) Programme. Manchester Brain Bank also receives Service Support costs from Medical Research Council. This work was supported by Medical Research Council of UK, Grant Number G0701441 and was also partially funded by a Wellcome Trust Strategic Award (Grant Number: 098330/Z/12/Z) conferred upon The London Down Syndrome (Lon-DownS) Consortium., HAL-UPMC, Gestionnaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Team 4 'NeoVasc' - INSERM U1245

Subjects
0301 basic medicine, Apolipoprotein E, Male, APP mutations, Down syndrome, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Plaque, Amyloid, Amyloid plaques, Amyloid beta-Protein Precursor, 0302 clinical medicine, Gene Frequency, Gene Duplication, Genotype, Amyloid precursor protein, Missense mutation, Aged, 80 and over, biology, Middle Aged, 3. Good health, Female, Cerebral amyloid angiopathy, Alzheimer’s disease, Adult, Amyloid, Mutation, Missense, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Apolipoproteins E, Alzheimer Disease, mental disorders, Journal Article, medicine, Humans, cardiovascular diseases, Allele, Allele frequency, Aged, Original Paper, business.industry, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, nutritional and metabolic diseases, medicine.disease, Cerebral Amyloid Angiopathy, 030104 developmental biology, Immunology, biology.protein, Blood Vessels, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

In this study, we have compared the severity of amyloid plaque formation and cerebral amyloid angiopathy (CAA), and the subtype pattern of CAA pathology itself, between APP genetic causes of AD (APPdup, APP mutations), older individuals with Down syndrome (DS) showing the pathology of Alzheimer’s disease (AD) and individuals with sporadic (early and late onset) AD (sEOAD and sLOAD, respectively). The aim of this was to elucidate important group differences and to provide mechanistic insights related to clinical and neuropathological phenotypes. Since lipid and cholesterol metabolism is implicated in AD as well as vascular disease, we additionally aimed to explore the role of APOE genotype in CAA severity and subtypes. Plaque formation was greater in DS and missense APP mutations than in APPdup, sEOAD and sLOAD cases. Conversely, CAA was more severe in APPdup and missense APP mutations, and in DS, compared to sEOAD and sLOAD. When stratified by CAA subtype from 1 to 4, there were no differences in plaque scores between the groups, though in patients with APPdup, APP mutations and sEOAD, types 2 and 3 CAA were more common than type 1. Conversely, in DS, sLOAD and controls, type 1 CAA was more common than types 2 and 3. APOE ε4 allele frequency was greater in sEOAD and sLOAD compared to APPdup, missense APP mutations, DS and controls, and varied between each of the CAA phenotypes with APOE ε4 homozygosity being more commonly associated with type 3 CAA than types 1 and 2 CAA in sLOAD and sEOAD. The differing patterns in CAA within individuals of each group could be a reflection of variations in the efficiency of perivascular drainage, this being less effective in types 2 and 3 CAA leading to a greater burden of CAA in parenchymal arteries and capillaries. Alternatively, as suggested by immunostaining using carboxy-terminal specific antibodies, it may relate to the relative tissue burdens of the two major forms of Aβ, with higher levels of Aβ40 promoting a more ‘aggressive’ form of CAA, and higher levels of Aβ42(3) favouring a greater plaque burden. Possession of APOE ε4 allele, especially ε4 homozygosity, favours development of CAA generally, and as type 3 particularly, in sEOAD and sLOAD. Electronic supplementary material The online version of this article (10.1007/s00401-018-1866-3) contains supplementary material, which is available to authorized users.

Published
2018

35. In utero seizures revealing dentato-olivary dysplasia caused by SCN2A mutation

Author

Dominique Carles, Christophe Pécheux, Gwenaëlle André, Fanny Sauvestre, Bernard Broussin, Caroline Lacoste, Laurent Villard, Fanny Pelluard, Sébastien Moutton, Nada Houcinat, Annie Laquerrière, Catherine Badens, Florent Marguet, Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence maladie rare Thalassémie, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)

Subjects
Pathology, medicine.medical_specialty, Histology, Encephalopathy, medicine.disease_cause, Bioinformatics, Pathology and Forensic Medicine, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Genetic linkage, Physiology (medical), medicine, Gene, ComputingMilieux_MISCELLANEOUS, Mutation, 030219 obstetrics & reproductive medicine, business.industry, medicine.disease, 3. Good health, Neurology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Dysplasia, In utero, Autism, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Most early-onset epileptic encephalopathies (EOEE) are caused by genetic defects. In the past, mutations, especially in genes encoding sodium channels, have been identified using linkage studies, array-CGH and more recently next-generation sequencing (NGS) [1]. Mutations in SCN2A gene have been identified in a wide variety of early-onset epileptic syndromes including benign familial neonatal infantile seizures (BFNIS) [2] and more severe forms leading to encephalopathy such as Ohtahara or West syndromes [3], epilepsy of infancy with migrating focal seizures (EIMFS) [4] and autism spectrum disorders [5]. In 2013, mutations in SCN2A gene were reported with dentato-olivary dysplasia (DOD) in a single family [6] but the link between DOD and severe EOEE needs to be confirmed [6]. This article is protected by copyright. All rights reserved.

Published
2017

36. Deep intronic hotspot variant explaining rhabdoid tumor predisposition syndrome in two patients with atypical teratoid and rhabdoid tumor

Author

Pascale Varlet, Laurence Brugières, Thierry Frebourg, Annie Laquerrière, Gaëlle Pierron, Stéphanie Puget, Olivier Delattre, Julien Masliah-Planchon, Franck Bourdeaut, Damien Bodet, Christelle Dufour, Arnault Tauziède-Espariat, Emmanuèle Lechapt-Zalcman, Pascale Schneider, CH Belfort-Montbéliard, Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Service de neurochirurgie 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), Centre de Psychiatrie et Neurosciences (U894), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hémato-immuno-oncologie pédiatrique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Hypoxie, physiopathologies cérébrovasculaire et tumorale (CERVOxy), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Unit of Somatic Genomics, Department of Genetics, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Somatique, Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and TAN, Yossan-Var

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Short Report, Biology, Bioinformatics, Germline, Rhabdoid Tumor Predisposition Syndrome, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Molecular genetics, Genetics, medicine, Humans, SMARCB1, Cells, Cultured, Germ-Line Mutation, Rhabdoid Tumor, Genetics (clinical), Teratoma, Cytogenetics, Infant, SMARCB1 Protein, Introns, Human genetics, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, 030220 oncology & carcinogenesis, Medical genetics, [SDV.IMM]Life Sciences [q-bio]/Immunology
Abstract

About one third of patients with rhabdoid tumors (RT) harbor a heterozygous germline variant in SMARCB1. Molecular diagnosis therefore keeps a crucial place in the diagnosis of RT, and genetic counseling should be systematically recommended. However, immunohistochemistry has progressively replaced molecular tools to assess the status of SMARCB1 in tumors; the necessity of analyzing SMARCB1 status in the tumor may thus be less considered by neuropathologists and pediatric neuro-oncologists. In the present manuscript as aforementioned, we report on two patients with bifocal RT in the first month of life and in whom no germline variant was initially found in the SMARCB1 coding sequence. Careful analysis of SMARCB1 status in the tumors revealed that only one of the two inactivating hits was found in the coding sequence. By sequencing the tumor cells RNA, we were able to detect an insertion with an abnormal sequence, due to the same intronic variant of SMARCB1, which led to the exonisation of the first intron. This cryptic variant was absent in the germline DNA of both patients. Of note, we previously reported one patient with the same deep intronic variant in the germline in a soft tissue RT. To our mind, this additional report on two patients clearly demonstrates that this intronic variant is a new hotspot that should now be systematically added to the germline screening of SMARCB1. We therefore recommend searching for and cautiously interpreting germline analysis if SMARCB1 has not been extensively studied in the tumor.

Published
2017

37. Autopsy findings in EPG5-related Vici syndrome with antenatal onset

Author

Annie Laquerrière, Florent Marguet, Heinz Jungbluth, Susan Byrne, Carmen Adina Petcu, Shehla Mohammed, Shu Yau, Mathias Gautel, Laurent Guibaud, R. Mein, and Renaud Touraine

Subjects
0301 basic medicine, medicine.medical_specialty, Microcephaly, Pediatrics, Vesicular Transport Proteins, Cardiomyopathy, Autophagy-Related Proteins, Autopsy, Cataract, Consanguinity, 03 medical and health sciences, Fetus, 0302 clinical medicine, Cataracts, Prenatal Diagnosis, Internal medicine, Genetics, medicine, Humans, Vici syndrome, Global developmental delay, Age of Onset, Genetics (clinical), Neuropathology, Hypopigmentation, business.industry, Immunologic Deficiency Syndromes, Lysosome-Associated Membrane Glycoproteins, Proteins, Fetal medicine, medicine.disease, Magnetic Resonance Imaging, Aicardi Syndrome, Phenotype, 030104 developmental biology, Endocrinology, EPG5 gene, Mutation, Failure to thrive, Agenesis of Corpus Callosum, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Vici syndrome is one of the most extensive inherited human multisystem disorders and due to recessive mutations in EPG5 encoding a key autophagy regulator with a crucial role in autophagosome-lysosome fusion. The condition presents usually early in life, with features of severe global developmental delay, profound failure to thrive, (acquired) microcephaly, callosal agenesis, cataracts, cardiomyopathy, hypopigmentation, and combined immunodeficiency. Clinical course is variable but usually progressive and associated with high mortality. Here, we present a fetus, offspring of consanguineous parents, in whom callosal agenesis and other developmental brain abnormalities were detected on fetal ultrasound scan (US) and subsequent MRI scan in the second trimester. Postmortem examination performed after medically indicated termination of pregnancy confirmed CNS abnormalities and provided additional evidence for skin hypopigmentation, nascent cataracts, and hypertrophic cardiomyopathy. Genetic testing prompted by a suggestive combination of features revealed a homozygous EPG5 mutation (c.5870-1G>A) predicted to cause aberrant splicing of the EPG5 transcript. Our findings expand the phenotypical spectrum of EPG5-related Vici syndrome and suggest that this severe condition may already present in utero. While callosal agenesis is not an uncommon finding in fetal medicine, additional presence of hypopigmentation, cataracts and cardiomyopathy is rare and should prompt EPG5 testing.

Published
2017

38. Non-invasive detection of somatic mutations using next-generation sequencing in primary central nervous system lymphoma

Author

Fabrice Jardin, Hervé Tilly, Elodie Bohers, Annie Laquerrière, Maxime Fontanilles, Florent Marguet, Catherine Maingonnat, Jean Michel Picquenot, Stéphane Derrey, Sylvain Mareschal, Elena Liana Veresezan, Pierre-Julien Viailly, Philippe Bertrand, Sydney Dubois, Vincent Camus, Philippe Ruminy, Stéphane Leprêtre, Laboratoire d'hématologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pathology, Rouen University Hospital, Service d'Hématologie Becquerel, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Département de Pathologie [CHU Rouen], Service de neurochirurgie [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), and Service d'Anatomie et Cytologie Pathologique [CHU Rouen]

Subjects
0301 basic medicine, Oncology, Male, Pathology, Lymphoma, Biopsy, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Central Nervous System Neoplasms, circulating cell-free tumor DNA, 0302 clinical medicine, Gene Frequency, somatic mutation, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, Primary central nervous system lymphoma, High-Throughput Nucleotide Sequencing, DNA, Neoplasm, Genomics, Middle Aged, Magnetic Resonance Imaging, 3. Good health, 030220 oncology & carcinogenesis, Female, DNA, Circular, Personal genomics, Research Paper, medicine.medical_specialty, Sensitivity and Specificity, DNA sequencing, 03 medical and health sciences, Germline mutation, Internal medicine, medicine, Humans, Liquid biopsy, Alleles, Aged, primary central nervous system lymphoma, liquid biopsy, business.industry, Cancer, Ion semiconductor sequencing, medicine.disease, 030104 developmental biology, Case-Control Studies, Mutation, next-generation sequencing, Personalized medicine, business
Abstract

// Maxime Fontanilles 1, 2 , Florent Marguet 3, 4 , Elodie Bohers 2 , Pierre-Julien Viailly 2 , Sydney Dubois 2 , Philippe Bertrand 2 , Vincent Camus 1, 2 , Sylvain Mareschal 2 , Philippe Ruminy 2 , Catherine Maingonnat 2 , Stephane Lepretre 1 , Elena-Liana Veresezan 5 , Stephane Derrey 6 , Herve Tilly 1, 2 , Jean-Michel Picquenot 5 , Annie Laquerriere 3, 4 and Fabrice Jardin 1, 2 1 Department of Hematology, Cancer Center Henri Becquerel, 76000 Rouen, France 2 INSERM U1245, Cancer Center Henri Becquerel, Institute of Research and Innovation in Biomedicine (IRIB), University of Normandy, UNIVROUEN, 76000 Rouen, France 3 INSERM U1245 and Hopital Charles Nicolle, NeoVasc Team, University of Normandy, UNIVROUEN, CHU-Hopitaux de Rouen, 76031 Rouen, France 4 Department of Neuropathology, Hopital Charles Nicolle, Normandy Center for Genomic and Personalized Medicine, CHU-Hopitaux de Rouen, 76031 Rouen, France 5 Department of Pathology, Cancer Center Henri Becquerel, 76000 Rouen, France 6 Department of Neurosurgery, Hopital Charles Nicolle, CHU-Hopitaux de Rouen, 76031 Rouen, France Correspondence to: Fabrice Jardin, email: fabrice.jardin@chb.unicancer.fr Keywords: primary central nervous system lymphoma, circulating cell-free tumor DNA, somatic mutation, liquid biopsy, next-generation sequencing Received: March 08, 2017 Accepted: May 03, 2017 Published: June 01, 2017 ABSTRACT Purpose: Primary central nervous system lymphomas (PCNSL) have recurrent genomic alterations. The main objective of our study was to demonstrate that targeted sequencing of circulating cell-free DNA (cfDNA) released by PCNSL at the time of diagnosis could identify somatic mutations by next-generation sequencing (NGS). Patients and Methods: PlasmacfDNA and matched tumor DNA (tDNA) from 25 PCNSL patients were sequenced using an Ion Torrent Personal Genome Machine (Life Technologies ® ). First, patient-specific targeted sequencing of identified somatic mutations in tDNA was performed. Then, a second sequencing targeting MYD88 c.T778C was performed and compared to plasma samples from 25 age-matched control patients suffering from other types of cancer. Results: According to the patient-specific targeted sequencing, eight patients (32% [95% CI 15-54%]) had detectable somatic mutations in cfDNA. Considering MYD88 sequencing, six patients had the specific c.T778C alteration detected in plasma. Using a control group, the sensitivity was 24% [9-45%] and the specificity was 100%. Tumor volume or deep brain structure involvement did not influence the detection of somatic mutations in plasma. Conclusion: This pilot study provided evidence that somatic mutations can be detected by NGS in the cfDNA of a subset of patients suffering from PCNSL.

Published
2017

39. Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues

Author

Anne Boland, Marguerite Miguet, Jocelyn Laporte, Julie Dawn Thompson, Robert-Yves Carlier, Nicol C. Voermans, Pierre G. Carlier, Nicolas Dondaine, Nasim Vasli, Sophie Scheidecker, Xavière Lornage, Edmar Zanoteli, Nadège Calmels, Shay Ben-Shachar, Raphaël Schneider, Pascal Laforêt, Curtis Rogers, Annie Laquerrière, Benno Küsters, Laurent Pasquier, Michel Fardeau, Valérie Kremer, Tanya Stojkovic, Erik-Jan Kamsteeg, Celia Boutte, Laura Tanner, Valérie Biancalana, Claire Gasnier, Elise Schaefer, Alexandre Moerman, Norma B. Romero, Armelle Magot, Julie Perrier, Pascale Marcorelle, Bruno Eymard, Jean Pouget, Jean-François Deleuze, Elisabeth Ollagnon-Roman, Christine Tranchant, Osorio Abath Neto, Nathalie Streichenberger, Sandra Mercier, Karine Nguyen, Helen Roper, Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Université Toulouse - Jean Jaurès (UT2J), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hôpital de la Timone [CHU - APHM] (TIMONE), Service de génétique clinique, hôpital Sud, Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut NeuroMyoGène (INMG), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Université du Québec à Rimouski (UQAR), Physiopathologie du système nerveux., Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Sciences Moléculaires de Marseille (ISM2), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), AFM-16992, AFM-Téléthon, ANR-10-IDEX-0002-02, Agence Nationale de la Recherche, DBI20131228569, Fondation pour la Recherche Médicale, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Université de Strasbourg, ANR-10-INBS-09, Agence Nationale pour la Recherche, Fondation Maladies Rares, CREGEMES, Université de Toulouse (UT), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)

Subjects
0301 basic medicine, Pathology, Severity of Illness Index, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Cohort Studies, 0302 clinical medicine, Respiratory function, Child, ComputingMilieux_MISCELLANEOUS, Congenital myopathy, Facial weakness, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Protein Tyrosine Phosphatases, Non-Receptor, X-linked myotubular myopathy, 3. Good health, X inactivation, Phenotype, Child, Preschool, Female, medicine.symptom, Myopathies, Structural, Congenital, Adult, Weakness, medicine.medical_specialty, Heterozygote, MTM1, Adolescent, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Pathology and Forensic Medicine, Diagnosis, Differential, 03 medical and health sciences, Cellular and Molecular Neuroscience, medicine, Humans, Centronuclear myopathy, Myopathy, Skewed X-inactivation, Aged, medicine.disease, 030104 developmental biology, Mutation, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), 030217 neurology & neurosurgery
Abstract

Contains fulltext : 182328.pdf (Publisher’s version ) (Closed access) X-linked myotubular myopathy (XLMTM), a severe congenital myopathy, is caused by mutations in the MTM1 gene located on the X chromosome. A majority of affected males die in the early postnatal period, whereas female carriers are believed to be usually asymptomatic. Nevertheless, several affected females have been reported. To assess the phenotypic and pathological spectra of carrier females and to delineate diagnostic clues, we characterized 17 new unrelated affected females and performed a detailed comparison with previously reported cases at the clinical, muscle imaging, histological, ultrastructural and molecular levels. Taken together, the analysis of this large cohort of 43 cases highlights a wide spectrum of clinical severity ranging from severe neonatal and generalized weakness, similar to XLMTM male, to milder adult forms. Several females show a decline in respiratory function. Asymmetric weakness is a noteworthy frequent specific feature potentially correlated to an increased prevalence of highly skewed X inactivation. Asymmetry of growth was also noted. Other diagnostic clues include facial weakness, ptosis and ophthalmoplegia, skeletal and joint abnormalities, and histopathological signs that are hallmarks of centronuclear myopathy such as centralized nuclei and necklace fibers. The histopathological findings also demonstrate a general disorganization of muscle structure in addition to these specific hallmarks. Thus, MTM1 mutations in carrier females define a specific myopathy, which may be independent of the presence of an XLMTM male in the family. As several of the reported affected females carry large heterozygous MTM1 deletions not detectable by Sanger sequencing, and as milder phenotypes present as adult-onset limb-girdle myopathy, the prevalence of this myopathy is likely to be greatly underestimated. This report should aid diagnosis and thus the clinical management and genetic counseling of MTM1 carrier females. Furthermore, the clinical and pathological history of this cohort may be useful for therapeutic projects in males with XLMTM, as it illustrates the spectrum of possible evolution of the disease in patients surviving long term.

Published
2017

40. Neuropathological Hallmarks of Brain Malformations in Extreme Phenotypes Related to DYNC1H1 Mutations

Author

Annie Laquerrière, Florent Marguet, Arnaud Molin, Guillaume Benoist, Marie Blouet, Camille Maillard, Carla Fernandez, Mara Cavallin, Nadia Bahi-Buisson, Jamel Chelly, Sophie Thomas, Françoise Chapon, Karine Poirier, Sabine Sigaudy, SOREL, EVE, Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement (Néovasc), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-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), Embryology and genetics of human malformation (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), Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Mobilités : Vieillissement, Pathologie, Santé (COMETE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Radiologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Université de Lausanne = University of Lausanne (UNIL), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-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), Centre de Biologie pour la Gestion des Populations (UMR CBGP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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 National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Université de Lausanne (UNIL), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)

Subjects
0301 basic medicine, Adult, Cytoplasmic Dyneins, Microcephaly, [SDV]Life Sciences [q-bio], Cell Culture Techniques, Subventricular zone, [SHS.PSY]Humanities and Social Sciences/Psychology, Biology, Corpus callosum, Protein Structure, Secondary, Pathology and Forensic Medicine, [SHS.PSY] Humanities and Social Sciences/Psychology, 03 medical and health sciences, Cellular and Molecular Neuroscience, Dysgenesis, 0302 clinical medicine, Fetus, Neuroblast, Pregnancy, medicine, Polymicrogyria, Humans, DYNC1H1 gene mutations, Neuropathology, ComputingMilieux_MISCELLANEOUS, [SCCO.NEUR]Cognitive science/Neuroscience, Neurogenesis, [SCCO.NEUR] Cognitive science/Neuroscience, Brain, General Medicine, Path finding, medicine.disease, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Phenotype, Neurology, Mutation, Female, Neurology (clinical), Brainstem, Brain pathology, Neuritic outgrowth, Neuroscience, 030217 neurology & neurosurgery
Abstract

International audience; Dyneins play a critical role in a wide variety of cellular functions such as the movement of organelles and numerous aspects of mitosis, making it central player in neocortical neurogenesis and migration. Recently, cytoplasmic dynein-1, heavy chain-1 (DYNC1H1) mutations have been found to cause a wide spectrum of brain cortical malformations. We report on the detailed neuropathological features of brain lesions from 2 fetuses aged 36 and 22 weeks of gestation (WG), respectively, carrying de novo DYNC1H1 mutations, p.Arg2720Lys and p.Val3951Ala and presenting the most severe phenotype reported to date. Analysis using the Dictyostelium discoideum dynein motor crystal structure showed that the mutations are both predicted to have deleterious consequences on the function of the motor domain. Both fetuses showed a similar macroscopic and histological brain malformative complex associating bilateral fronto-parietal polymicrogyria (PMG), dysgenesis of the corpus callosum and of the cortico-spinal tracts, along with brainstem and cerebellar abnormalities. Both exhibited extremely severe disrupted cortical lamination. Immunohistochemical studies provided the evidence for defects in cell proliferation and postmitotic neuroblast ability to exit from the subventricular zone resulting in a failure of radial migration toward the cortical plate, thus providing new insights for the understanding of the pathophysiology in these cortical malformations.

Published
2017

41. Loss-of-Function Mutations in LGI4, a Secreted Ligand Involved in Schwann Cell Myelination, Are Responsible for Arthrogryposis Multiplex Congenita

Author

Loic Quevarec, Florent Marguet, Bruno Reversade, Martine Bucourt, Ivo Gut, Mohammad Shboul, Jérome Maluenda, Alvin Yu Jin Ng, Shifeng Xue, Jacinda B. Sampson, Luc Rigonnot, Annie Laquerrière, Sandra Whalen, Carolina Tesi Rocha, Thong Teck Tan, Sumanty Tohari, Fawaz Alkazaleh, Carine Bonnard, Byrappa Venkatesh, Kristin G. Monaghan, Marta Gut, Marie Gonzales, Carly E. Siskind, Mung Kei Kong, Judith Melki, Megan T. Cho, Center for Reproductive Medicine, Amsterdam Reproduction & Development (AR&D), ACS - Heart failure & arrhythmias, and ACS - Diabetes & metabolism

Subjects
0301 basic medicine, Male, ADAM22, Schwann cell, Nerve Tissue Proteins, 030105 genetics & heredity, Biology, 03 medical and health sciences, Myelin, Immunolabeling, Germline mutation, Report, Genetics, medicine, Humans, Genetics (clinical), Loss function, Myelin Sheath, Arthrogryposis, Arthrogryposis multiplex congenital, Extracellular Matrix Proteins, Arthrogryposis multiplex congenita, Peripheral hypomyelination, Infant, Newborn, Secreted ligand, Infant, Molecular biology, Pedigree, 030104 developmental biology, medicine.anatomical_structure, Whole-exome sequencing, Child, Preschool, Mutation, Female, LGI4, Schwann Cells, medicine.symptom, Hypomyelination
Abstract

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4-deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC.

Published
2017

42. Pyridoxine-dependent epilepsy: report on three families with neuropathology

Author

Florent Marguet, Annie Laquerrière, Abdellah Tebani, Stéphane Marret, Lenaig Abily-Donval, M. Brasseur-Daudruy, Fethi Bayoudh, Stéphanie Torre, Hager Barakizou, Sami Jebnoun, Soumeya Bekri, Department of Pathology, Rouen University Hospital, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement (Néovasc), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Team 4 'NeoVasc' - INSERM U1245, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital militaire-Tunis, Service d'imagerie médicale [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-Hôpital Charles Nicolle [Rouen]-CHU Rouen, Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Laboratoire de biochimie générale [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Centre hospitalier universitaire de Rouen

Subjects
0301 basic medicine, Male, Pathology, medicine.medical_specialty, Neurology, [SDV]Life Sciences [q-bio], Encephalopathy, Autopsy, Neuropathology, Biochemistry, Gastroenterology, 03 medical and health sciences, Cellular and Molecular Neuroscience, Epilepsy, 0302 clinical medicine, Fatal Outcome, Internal medicine, medicine, Humans, Child, Pyridoxine-dependent epilepsy, ComputingMilieux_MISCELLANEOUS, business.industry, Infant, Newborn, Infant, Pyridoxine, medicine.disease, 3. Good health, 030104 developmental biology, Gliosis, Child, Preschool, Dietary Supplements, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Pyridoxine-dependent epilepsy (PDE) is a pharmacoresistant epileptogenic encephalopathy controlled by pyridoxine supplementation at pharmacological doses. Despite supplementation, the long-term outcome is often poor possibly because of recurrent seizures and developmental structural brain abnormalities. We report on five patients with PDE from three unrelated families. The diagnosis was confirmed by ALDH7A1 sequencing, which allowed for the characterization of two homozygous variations [NM_001182.3:c.1279G > C - p.(Glu427Gln) and c.834G > A - p.(Val278Val)]. Brain autopsy was conducted for one untreated patient with molecularly confirmed antiquitin deficiency. Macroscopic and histological examination revealed a combination of lesions resulting from recurrent seizures and consisting of extensive areas of cortical necrosis, gliosis, and hippocampic sclerosis. The examination also revealed developmental abnormalities including corpus callosum dysgenesis and corticospinal pathfinding anomalies. This case is the second to be reported in the literature, and our findings show evidence that antiquitin is required for normal brain development and functioning. Despite prophylactic prenatal pyridoxine supplementation during the last trimester of pregnancy in one of the three families and sustained pyridoxine treatment in three living patients, the clinical outcome remained poor with delayed acquisition of neurocognitive skills. Combined therapy (pyridoxine/arginine supplementation and lysine-restricted diet) should be considered early in the course of the disease for a better long-term outcome. Enhanced knowledge of PDE features is required to improve treatment strategies.

Published
2016

43. Mutations in GLDN, Encoding Gliomedin, a Critical Component of the Nodes of Ranvier, Are Responsible for Lethal Arthrogryposis

Author

Loic Quevarec, Constance Manso, Annie Laquerrière, Jérôme Devaux, Fabien Guimiot, Florence Petit, Marta Gut, Florent Marguet, Marie Gonzales, Ivo Gut, Romulus Grigorescu, Sandra Whalen, Jérome Maluenda, Annick Toutain, Anne Dieux Coeslier, Alexandre J. Vivanti, Judith Melki, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Biologie du Développement, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Institut méditerranéen de biodiversité et d'écologie marine et continentale (IMBE), Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UMR237-Aix Marseille Université (AMU)-Avignon Université (AU), Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre for Genomic Regulation [Barcelona] (CRG), Universitat Pompeu Fabra [Barcelona] (UPF)-Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Centre Nacional D'Anàlisi Genómica, Parc Cientific de Barcelona, Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement (Néovasc), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Avignon Université (AU)-Aix Marseille Université (AMU)-Institut de recherche pour le développement [IRD] : UMR237-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-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), CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), 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), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Institut méditerranéen de biodiversité et d'écologie marine et continentale ( IMBE ), Université d'Avignon et des Pays de Vaucluse ( UAPV ) -Aix Marseille Université ( AMU ) -Institut de recherche pour le développement [IRD] : UMR237-Centre National de la Recherche Scientifique ( CNRS ), Anthropologie bio-culturelle, Droit, Ethique et Santé ( ADES ), Aix Marseille Université ( AMU ) -EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique ( CNRS ), Hôpital Bretonneau-CHRU Tours, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Génétique et Embryologie, Centre for Genomic Regulation [Barcelona] ( CRG ), Universitat Pompeu Fabra [Barcelona]-Centro Nacional de Analisis Genomico [Barcelona] ( CNAG ), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement ( Néovasc ), Institute for Research and Innovation in Biomedicine ( IRIB ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'Anatomie et Cytologie Pathologique [Rouen], CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Centre de recherche en neurobiologie - neurophysiologie de Marseille ( CRN2M ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre

Subjects
Male, 0301 basic medicine, Cell Adhesion Molecules, Neuronal, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Nerve Tissue Proteins, Biology, 03 medical and health sciences, 0302 clinical medicine, Genetic linkage, Report, Ranvier's Nodes, Genetics, medicine, Humans, Exome, Nerve Growth Factors, Fetal Death, Alleles, Genetics (clinical), Exome sequencing, ComputingMilieux_MISCELLANEOUS, Arthrogryposis, Arthrogryposis multiplex congenita, Cell adhesion molecule, Infant, Newborn, Membrane Proteins, Disease gene identification, Axons, Pedigree, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Peripheral nervous system, Mutation, Female, Sciatic nerve, medicine.symptom, Cell Adhesion Molecules, 030217 neurology & neurosurgery, Protein Binding
Abstract

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through linkage analysis, homozygosity mapping, and exome sequencing in four unrelated families affected by lethal AMC, we identified biallelic mutations in GLDN in the affected individuals. GLDN encodes gliomedin, a secreted cell adhesion molecule involved in the formation of the nodes of Ranvier. Transmission electron microscopy of the sciatic nerve from one of the affected individuals showed a marked lengthening defect of the nodes. The GLDN mutations found in the affected individuals abolish the cell surface localization of gliomedin and its interaction with its axonal partner, neurofascin-186 (NF186), in a cell-based assay. The axoglial contact between gliomedin and NF186 is essential for the initial clustering of Na+ channels at developing nodes. These results indicate a major role of gliomedin in node formation and the development of the peripheral nervous system in humans. These data indicate that mutations of GLDN or CNTNAP1 (MIM: 616286), encoding essential components of the nodes of Ranvier and paranodes, respectively, lead to inherited nodopathies, a distinct disease entity among peripheral neuropathies.

Published
2016

44. Giant epidermoid cyst of the occipital area with bone invasion: A case report

Author

Alorini, Mohammed, Vianney, Gilard, Florent, Marguet, Olivier, Langlois, and Annie, Laquerrière

Subjects
Bone invasion, integumentary system, parasitic diseases, occipital area, otorhinolaryngologic diseases, Original Article, Giant epidermoid cyst, neoplasms
Abstract

Epidermoid cysts are slowly growing pseudotumors usually measuring

Published
2018

45. Clinical and Molecular Characterization of Patients with Mucopolysaccharidosis Type I in an Algerian Series

Author

Lahouaria Zanoutene-Cheriet, Abla Chalabi Benabdellah, Zoubir Adjtoutah, Annie Laquerrière, Abdellah Tebani, Carole Brasse-Lagnel, Soumeya Bekri, Lenaig Abily-Donval, Stéphane Marret, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Rouen, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement (Néovasc), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-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), Team 4 'NeoVasc' - INSERM U1245, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Laboratoire de biochimie générale [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Centre hospitalier universitaire de Rouen

Subjects
0301 basic medicine, Male, Pathology, Mucopolysaccharidosis I, [SDV]Life Sciences [q-bio], Compound heterozygosity, lcsh:Chemistry, chemistry.chemical_compound, Consanguinity, Iduronidase, Child, lcsh:QH301-705.5, Spectroscopy, ComputingMilieux_MISCELLANEOUS, Communication, mucopolysaccharidosis type I, General Medicine, 3. Good health, Computer Science Applications, Child, Preschool, Female, medicine.medical_specialty, Adolescent, Proline, IDUA, Biology, Arginine, Polymorphism, Single Nucleotide, dermatan sulfate, Catalysis, Dermatan sulfate, Inorganic Chemistry, 03 medical and health sciences, Mucopolysaccharidosis type I, Young Adult, medicine, Humans, Physical and Theoretical Chemistry, Allele, GAGs, Molecular Biology, Organic Chemistry, heparin sulfate, Infant, medicine.disease, 030104 developmental biology, chemistry, lcsh:Biology (General), lcsh:QD1-999, Algeria, Scheie syndrome
Abstract

Mucopolysaccharidoses (MPS’s) represent a subgroup of lysosomal storage diseases related to a deficiency of enzymes that catalyze glycosaminoglycans degradation. Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder caused by a deficiency of α-l-iduronidase encoded by the IDUA gene. Partially degraded heparan sulfate and dermatan sulfate accumulate progressively and lead to multiorgan dysfunction and damage. The aim of this study is to describe the clinical, biochemical, and molecular characteristics of 13 Algerian patients from 11 distinct families. MPS I diagnosis was confirmed by molecular study of the patients’ IDUA gene. Clinical features at the diagnosis and during the follow-up are reported. Eighty-four percent of the studied patients presented with a mild clinical phenotype. Molecular study of the IDUA gene allowed the characterization of four pathological variations at the homozygous or compound heterozygote status: IDUA NM_00203.4:c.1598C>G-p.(Pro533Arg) in 21/26 alleles, IDUA NM_00203.4:c.532G>A-p.(Glu178Lys) in 2/26 alleles, IDUA NM_00203.4:c.501C>G-p.(Tyr167*) in 2/26 alleles, and IDUA NM_00203. 4: c.1743C>G-p.(Tyr581*) in 1/26 alleles. This molecular study unveils the predominance of p.(Pro533Arg) variation in our MPS I patients. In this series, the occurrence of some clinical features linked to the Scheie syndrome is consistent with the literature, such as systematic valvulopathies, corneal opacity, and umbilical hernia; however, storage signs, facial dysmorphic features, and hepatomegaly were more frequent in our series. Screening measures for these debilitating diseases in highly consanguineous at-risk populations must be considered a priority health problem.

Published
2016

46. Multiple acyl-CoA dehydrogenase deficiency (MADD) as a cause of late-onset treatable metabolic disease

Author

Pierre Kaminsky, Cécile Acquaviva-Bourdain, L Pérard, S. Souvannanorath, Christine Vianey-Saban, Bruno Eymard, Pascal Laforêt, Jean Pouget, Anthony Behin, A Fouilhoux, Guillaume Bassez, O Rigal, S. Attarian, Nathalie Streichenberger, A Labarre-Villa, C Vanhulle, M. Brivet, Annie Laquerrière, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL)

Subjects
Adult, Iron-Sulfur Proteins, Male, 0301 basic medicine, medicine.medical_specialty, Weakness, Electron-Transferring Flavoproteins, Biopsy, [SDV]Life Sciences [q-bio], Exercise intolerance, Compound heterozygosity, Gastroenterology, Lipid Metabolism, Inborn Errors, Rhabdomyolysis, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Carnitine, Internal medicine, Humans, Medicine, Age of Onset, Multiple Acyl Coenzyme A Dehydrogenase Deficiency, Muscle, Skeletal, Multiple Acyl-CoA Dehydrogenase Deficiency, Exercise, Oxidoreductases Acting on CH-NH Group Donors, Muscle biopsy, medicine.diagnostic_test, Electromyography, business.industry, Muscle weakness, Neuromuscular Diseases, Middle Aged, medicine.disease, 3. Good health, 030104 developmental biology, Endocrinology, Mitochondrial respiratory chain, Neurology, Mutation, Female, France, Neurology (clinical), medicine.symptom, business, Oxidation-Reduction, 030217 neurology & neurosurgery
Abstract

Introduction Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare, treatable, beta-oxidation disorder responsible for neuromuscular symptoms in adults. This case series describes the clinical and biochemical features of 13 French patients with late-onset MADD. Methods and results Thirteen ambulant patients (eight women, five men), with a median age at onset of 27 years, initially experienced exercise intolerance (n = 9), isolated muscle weakness (n = 1) and a multisystemic pattern with either central nervous system or hepatic dysfunction (n = 3). During the worsening period, moderate rhabdomyolysis (n = 5), a pseudomyasthenic pattern (n = 5) and acute respiratory failure (n = 1) have been observed. Weakness typically affected the proximal limbs and axial muscles, and there was sometimes facial asymmetry (n = 3). Moderate respiratory insufficiency was noted in one case. Median baseline creatine kinase was 190 IU/L. Lactacidemia was sometimes moderately increased at rest (3/10) and after exercise (1/3). The acylcarnitine profile was characteristic, with increases in all chain-length acylcarnitine species. Electromyography revealed a myogenic pattern, while muscle biopsy showed lipidosis, sometimes with COX-negative fibers (n = 2). The mitochondrial respiratory chain was impaired in five cases, with coenzyme Q10 decreased in two cases. All patients harbored mutations in the ETFDH gene (four homozygous, seven compound heterozygous, two single heterozygous), with nine previously unidentified mutations. All patients were good responders to medical treatment, but exercise intolerance and/or muscular weakness persisted in 11 of them. Conclusion Late-onset forms of MADD may present as atypical beta-oxidation disorders. Acylcarnitine profiling and muscle biopsy remain the most decisive investigations for assessing the diagnosis. These tests should thus probably be performed more widely, particularly in unexplained cases of neuromuscular and multisystemic disorders.

Published
2016

47. Prognostic and Therapeutic Markers in Chordomas: A Study of 287 Tumors

Author

Annie Laquerrière, Bernard George, Jean-Luc Prétet, Loïc Feuvret, Schahrazed Bouazza, François Labrousse, Homa Adle-Biassette, Eleonora Aronica, Séverine Valmary-Degano, Sébastien Froelich, Fabrice Projetti, Henri Salle, Marc Polivka, Marc Pocard, Marie-Hélène Aubriot-Lorton, Arnault Tauziède-Espariat, Loic Chaigneau, Franck Monnien, Philippe Herman, Nicolas Isambert, Damien Bresson, Cellular and Computational Neuroscience (SILS, FNWI), ANS - Cellular & Molecular Mechanisms, Pathology, APH - Amsterdam Public Health, Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Lariboisière-Fernand-Widal [APHP], Hôpital Lariboisière, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Limoges (UNILIM), Genome Analysis, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'Anatomie Pathologique [CHU Limoges], CHU Limoges, Laboratoire de Neurobiologie des Réseaux Sensorimoteurs (LNRS), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5), and Service de Neurochirurgie [CHU Limoges]

Subjects
Oncology, Male, Pathology, Neoplasm, Residual, MESH: Neoplasm Grading, Apoptosis, medicine.disease_cause, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, MESH: Child, Epidermal growth factor receptor, Child, MESH: Cohort Studies, MESH: Aged, Univariate analysis, MESH: Middle Aged, biology, MESH: Infant, Newborn, General Medicine, Middle Aged, Prognosis, MESH: Infant, Immunohistochemistry, 3. Good health, Vascular endothelial growth factor, Neurology, MESH: Young Adult, MESH: Survival Analysis, 030220 oncology & carcinogenesis, Child, Preschool, Female, MESH: Biomarkers, Tumor, KRAS, Protons, Adult, medicine.medical_specialty, Adolescent, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Prognosis, Disease-Free Survival, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Necrosis, Young Adult, Internal medicine, medicine, Biomarkers, Tumor, Chordoma, Humans, neoplasms, MESH: Neoplasm, Residual, PI3K/AKT/mTOR pathway, Survival analysis, Aged, Retrospective Studies, MESH: Adolescent, MESH: Necrosis, MESH: Humans, business.industry, MESH: Apoptosis, MESH: Child, Preschool, Infant, Newborn, MESH: Chordoma, Infant, MESH: Adult, MESH: Retrospective Studies, MESH: Immunohistochemistry, Retrospective cohort study, medicine.disease, Survival Analysis, MESH: Male, chemistry, MESH: Disease-Free Survival, biology.protein, MESH: Protons, Neurology (clinical), Neoplasm Grading, business, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; Chordomas are slow-growing malignant neoplasms. Determination of histopathologic prognostic factors using a large cohort study has been limited by their low incidence. In this retrospective study, we investigated the clinical, histopathologic, and immunohistochemical prognostic factors in 287 chordomas from 111 patients assessed by central pathologic review. Expression patterns of a variety of markers, including vascular endothelial growth factor (VEGF), mTOR pathway, c-kit, HER2, epidermal growth factor receptor (EGFR) and STAT3, and KRAS, BRAF, EGFR, and PIK3CA mutations were analyzed. On univariate analysis, the results confirm surgery as the best treatment, as judged by patient progression-free survival (PFS) and overall survival (OS). Proton therapy, the presence of a dedifferentiated component, mitotic figures, and Ki67 and p53 labeling indices correlated with PFS . Necrosis and apoptosis correlated with OS. Based on these findings, we propose a histopathologic grading system that correlates with PFS and OS. On multivariate analysis, extent of resection, tumor grade, and proton therapy were independent prognostic factors of PFS; extent of resection, tumor location, and grade were independent prognostic factors of OS. Based on the expression of EGFR, pSTAT3, VEGF, and mTOR pathway proteins, (in 85.9%, 79.1%, 85.7%, and 46% of chordomas, respectively), and 2 new mutations in the PIK3CA gene, we also provide evidence for potential therapeutic targets.

Published
2016

48. Somatic Mutations Detected in Plasma Cell-Free DNA By Targeted Sequencing: Assessment of Liquid Biopsy in Primary Central Nervous System Lymphoma

Author

Philippe Ruminy, Maxime Fontanilles, Fabrice Jardin, Vincent Camus, Florent Marguet, Jean-Michel Picquenot, Sylvain Mareschal, Annie Laquerrière, Elena-Liana Veresezan, Pierre-Julien Viailly, Hervé Tilly, Elodie Bohers, Philippe Bertrand, Sydney Dubois, Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Département de Pathologie [CHU Rouen], and Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)

Subjects
Oncology, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Immunology, Plasma cell, Biology, medicine.disease_cause, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, CDKN2A, Internal medicine, medicine, Liquid biopsy, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Mutation, Primary central nervous system lymphoma, Cell Biology, Hematology, CD79B, medicine.disease, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Diffuse large B-cell lymphoma
Abstract

Background Primary Central Nervous System Lymphoma (PCNSL) are rare and aggressive primary brain tumors. Histological diagnosis can be difficult at initial stages or at relapse due to deep brain structure involvement. Finding a minimally invasive biomarker aiding the diagnosis remains an unsolved question. Plasma Cell-Free DNA (cfDNA) seems to have shown its diagnostic and prognostic value in nodal Diffuse Large B Cell Lymphomas (DLBCL) [Roschewski et al, Lancet Oncology, 2015; Kurtz et al, Blood, 2015]. Our main objective was to demonstrate that targeted sequencing of cfDNA in plasma at time of diagnosis could identify PCNSL somatic mutations. Methods 30 immuno-competent patients suffering from newly diagnosed PCNSL, without any extranevraxic lesions, were enrolled from 2008 to 2014. Tumor tissues and plasma samples were collected at the time of diagnosis and frozen until use. High throughput sequencing was performed on primitive tumors using a panel of 34 genes relevant to lymphomagenesis, as previously reported [Dubois et al, Oncotarget, 2015; Bohers et al, Haematologica, 2015]. We next performed patient-specific targeted sequencing of identified somatic mutations in cfDNA. The detection sensitivity threshold was set at 1% for all SNVs, except for MYD88 L265P, which was set at 0.1%. The primary endpoint was the proportion of patients having at least one somatic mutation found in the plasma. Results Among 24 available plasmas, 15 patients (63%) had at least one detected somatic mutation in cfDNA. All plasmas had detectable cfDNA (mean concentration 1.6 ng/µL). No correlation was found between tumor volume and cfDNA concentration (R squared coefficient 0.01). Regarding the whole sequenced cohort (n=30) 21 (70%) were classified as nonGC subtype, 8 (27%) as GC subtype and 1 patient (3%) as unclassifiable, according to the Hans algorithm. 29 tumors had at least one somatic mutation, mainly nonsynonymous single nucleotide variants (SNV). The NF-kB pathway was the most affected by mutations: MYD88 (n=23, 77%), PIM1 (n=11, 37%), TNFAIP3 (n=6, 20%), IRF4 (n=3, 10%), CARD11 (n=3, 10%) and PRDM1 (n=3, 10%). Among the 23 tumors harboring a MYD88 mutation, the L265P variant was the most frequent (20 patients, 67%); mean tumor variant allele frequency was 46% [min 8%, max 91%]. One tumor harbored a single MYD88 L265P mutation with no other detectable abnormality. Among patients with both available plasma and a somatic MYD88 L265P mutation in the tumor, 15 patients (88%) had an identifiable L265P variant in cfDNA, with a mean variant allele frequency of 4% [min 0.1%, max 28%]. PIM1 and TNFAIP3 SNVs were also detected in cfDNA for respectively two and one patient. The second most affected pathway was the apoptotic pathway: genes affected by mutations included GNA13 (n=7, 23%), TP53 (n=2, 7%), MYC (n=1, 3%), CDKN2A (n=2, 7%) and BCL2 (n=1, 3%). The B Cell Receptor (BCR) pathway was also affected, mainly due to mutations targeting CD79B (n=10, 33%) and ITPKB (n=3, 10%) mutations. 8 tumors (27%) harbored a dual alteration affecting MYD88 and CD79B. One tumor of the GC subtype had one EZH2 SNV (Y646H), but the mutation was not found in cfDNA. There was no significant difference in overall survival (OS) between patients with and without mutations detected in cfDNA: mean OS 27 months versus 18 months (HR 0.6; IC95% [0.2 - 1.6], p value 0.3). Tumor gene copy number variations were detected in 29/30 patients with either homo or heterozygous deletions or copy gains. CDKN2A/2B deletions were detected in 23 cases (77%). Conclusion To our knowledge this is the first study that provides evidence that somatic mutations can be detected in cfDNA in patients suffering from PCNSL, therefore constituting a minimally invasive tool helping for diagnosis. Further studies are now required to improve prognosis and predictive values of this new promising procedure for PCNSL patient care. Disclosures No relevant conflicts of interest to declare.

Published
2015

49. Lethal Neonatal Progression of Fetal Cardiomegaly Associated to ACAD9 Deficiency

Author

Annie Laquerrière, Stéphane Marret, Marie Crahes, Isabelle Ségalas-Milazzo, Caroline Lardennois, Stéphanie Torre, Laurence Menu-Bouaouiche, Jennifer Lagoutte-Renosi, Marlène Rio, Florian Renosi, Soumeya Bekri, Carole Brasse-Lagnel, Laboratoire de biochimie générale [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre hospitalier universitaire de Rouen, Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Normandie Université (NU), Laboratoire de Glycobiologie et Matrice Extracellulaire Végétale (Glyco-MEV), Normandie Université (NU)-Normandie Université (NU), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement (Néovasc), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Fetal cardiomegaly, medicine.medical_specialty, Mitochondrial respiratory chain, Dehydrogenase, Exercise intolerance, β-Oxidation, ACAD9, Bioinformatics, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Medicine, [CHIM]Chemical Sciences, Mitochondrial respiratory chain complex I, 030304 developmental biology, 0303 health sciences, business.industry, 3. Good health, Endocrinology, lipids (amino acids, peptides, and proteins), medicine.symptom, business, High homology, 030217 neurology & neurosurgery
Abstract

International audience; ACAD9 (acyl-CoA dehydrogenase 9) is an essential factor for the mitochondrial respiratory chain complex I assembly. ACAD9, a member of acyl-CoA dehydrogenase family, has high homology with VLCAD (very long-chain acyl-CoA dehydrogenase) and harbors a homodimer structure. Recently, patients with ACAD9 deficiency have been described with a wide clinical spectrum ranging from severe lethal form to moderate form with exercise intolerance.We report here a prenatal presentation with intrauterine growth retardation and cardiomegaly, with a fatal outcome shortly after birth. Compound heterozygous mutations, a splice-site mutation – c.1030-1G>T and a missense mutation – c.1249C>T; p.Arg417Cys, were identified in the ACAD9 gene. Their effect on protein structure and expression level was investigated. Protein modeling suggested a functional effect of the c.1030-1G>T mutation generating a non-degraded truncated protein and the p.Arg417Cys, creating an aberrant dimer. Our results underscore the crucial role of ACAD9 protein for cardiac function.

Published
2015

50. Signaling switch of the urotensin II vasosactive peptide GPCR: prototypic chemotaxic mechanism in glioma

Author

Je Joubert, Laurence Desrues, Céline Lecointre, François Proust, C Brulé, Po Guichet, Pierrick Gandolfo, Annie Laquerrière, Nicolas Perzo, Hélène Castel, Richard Leduc, Fabrice Morin, Marie Chabbert, Laurent Prézeau, V. Le Joncour, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de médecine et des sciences de la santé [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS), Institut de Génomique Fonctionnelle (IGF), 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), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement (Néovasc), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurochirurgie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Faculté de médecine et des sciences de la santé [Sherbrooke], Université de Sherbrooke [Sherbrooke], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Service d'Anatomie et Cytologie Pathologique [Rouen], Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Service de neurochirurgie [Rouen]

Subjects
Cancer Research, Biopsy, Urotensins, [SDV]Life Sciences [q-bio], Motility, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Polymerization, Receptors, G-Protein-Coupled, Focal adhesion, chemistry.chemical_compound, Genetics, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cell adhesion, Molecular Biology, Rho-associated protein kinase, PI3K/AKT/mTOR pathway, G protein-coupled receptor, Brain Neoplasms, Chemotaxis, Actins, Cell biology, chemistry, Biochemistry, Signal transduction, Urotensin-II, Glioblastoma, Signal Transduction
Abstract

International audience; Multiform glioblastomas (GBM) are the most frequent and aggressive primary brain tumors in adults. The poor prognosis is due to neo-angiogenesis and cellular invasion, processes that require complex chemotaxic mechanisms involving motility, migration and adhesion. Understanding these different cellular events implies identifying receptors and transduction pathways that lead to and promote either migration or adhesion. Here we establish that glioma express the vasoactive peptide urotensin II (UII) and its receptor UT and that UT-mediated signaling cascades are involved in glioma cell migration and adhesion. Components of the urotensinergic systems, UII and UT, are widely expressed in patient-derived GBM tissue sections, glioma cell lines and fresh biopsy explants. Interestingly, gradient concentrations of UII produced chemoattracting migratory/motility effects in glioma as well as HEK293 cells expressing human UT. These effects mainly involved the G13/Rho/rho kinase pathway while partially requiring Gi/o/PI3K components. In contrast, we observed that homogeneous concentrations of UII drastically blocked cell motility and stimulated cell–matrix adhesions through a UT/Gi/o signaling cascade, partially involving phosphatidylinositol-3 kinase. Finally, we provide evidence that, in glioma cells, homogeneous concentration of UII allowed translocation of Gα13 to the UT receptor at the plasma membrane and increased actin stress fibers, lamellipodia formation and vinculin-stained focal adhesions. UII also provoked a re-localization of UT precoupled to Gαi in filipodia and initiated integrin-stained focal points. Altogether, these findings suggest that UT behaves as a chemotaxic receptor, relaying a signaling switch between directional migration and cell adhesion under gradient or homogeneous concentrations, thereby redefining sequential mechanisms affecting tumor cells during glioma invasion. Taken together, our results allow us to propose a model in order to improve the design of compounds that demonstrate signaling bias for therapies that target specifically the Gi/o signaling pathway.

Published
2015

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