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1. Systematic analysis and prediction of genes associated with monogenic disorders on human chromosome X

Author

Elsa Leitão, Christopher Schröder, Ilaria Parenti, Carine Dalle, Agnès Rastetter, Theresa Kühnel, Alma Kuechler, Sabine Kaya, Bénédicte Gérard, Elise Schaefer, Caroline Nava, Nathalie Drouot, Camille Engel, Juliette Piard, Bénédicte Duban-Bedu, Laurent Villard, Alexander P. A. Stegmann, Els K. Vanhoutte, Job A. J. Verdonschot, Frank J. Kaiser, Frédéric Tran Mau-Them, Marcello Scala, Pasquale Striano, Suzanna G. M. Frints, Emanuela Argilli, Elliott H. Sherr, Fikret Elder, Julien Buratti, Boris Keren, Cyril Mignot, Delphine Héron, Jean-Louis Mandel, Jozef Gecz, Vera M. Kalscheuer, Bernhard Horsthemke, Amélie Piton, and Christel Depienne

Subjects
Science
Abstract

Discovering disease genes on the X chromosome can be particularly challenging. Here, the authors use features of known disease genes and machine learning to predict genes that remain to be associated with disorders on this chromosome.

Published
2022
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2. Mutations in the KIF21B kinesin gene cause neurodevelopmental disorders through imbalanced canonical motor activity

Author

Laure Asselin, José Rivera Alvarez, Solveig Heide, Camille S. Bonnet, Peggy Tilly, Hélène Vitet, Chantal Weber, Carlos A. Bacino, Kristin Baranaño, Anna Chassevent, Amy Dameron, Laurence Faivre, Neil A. Hanchard, Sonal Mahida, Kirsty McWalter, Cyril Mignot, Caroline Nava, Agnès Rastetter, Haley Streff, Christel Thauvin-Robinet, Marjan M. Weiss, Gladys Zapata, Petra J. G. Zwijnenburg, Frédéric Saudou, Christel Depienne, Christelle Golzio, Delphine Héron, and Juliette D. Godin

Subjects
Science
Abstract

Kinesins regulate intracellular transport and microtubule dynamics. Here, the authors show that KIF21B variants in humans associate with corpus callosum agenesis and microcephaly. Using mice and zebrafish, they showed the cellular mechanisms altered by the missense KIF21B variants.

Published
2020
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3. Exome Sequencing Reveals Signal Transduction Genes Involved in Impulse Control Disorders in Parkinson's Disease

Author

Sabine Prud'hon, Samir Bekadar, Agnès Rastetter, Justine Guégan, Florence Cormier-Dequaire, Lucette Lacomblez, Graziella Mangone, Hana You, Mailys Daniau, Yannick Marie, Hélène Bertrand, Suzanne Lesage, Sophie Tezenas Du Montcel, Mathieu Anheim, Alexis Brice, Fabrice Danjou, and Jean-Christophe Corvol

Subjects
Parkinson's disease (PD), dopamine agonists (DA), impulse control disorders (ICD), pharmacogenetics, exome sequencing, Neurology. Diseases of the nervous system, RC346-429
Abstract

Introduction: Impulse control disorders (ICDs) frequently complicate dopamine agonist (DA) therapy in Parkinson's disease (PD). There is growing evidence of a high heritability for ICDs in the general population and in PD. Variants on genes belonging to the reward pathway have been shown to account for part of this heritability. We aimed to identify new pathways associated with ICDs in PD.Methods: Thirty-six Parkinsonian patients on DA therapy with (n = 18) and without ICDs (n = 18) matched on age at PD's onset, and gender was selected to represent the most extreme phenotypes of their category. Exome sequencing was performed, and variants with a strong functional impact in brain-expressed genes were selected. Allele frequencies and their distribution in genes and pathways were analyzed with single variant and SKAT-O tests. The 10 most associated variants, genes, and pathways were retained for replication in the Parkinson's progression markers initiative (PPMI) cohort.Results: None of markers tested passed the significance threshold adjusted for multiple comparisons. However, the “Adenylate cyclase activating” pathway, one of the top associated pathways in the discovery data set (p = 1.6 × 10−3) was replicated in the PPMI cohort and was significantly associated with ICDs in a post hoc pooled analysis (combined p-value 3.3 × 10−5). Two of the 10 most associated variants belonged to genes implicated in cAMP and ERK signaling (rs34193571 in RasGRF2, p = 5 × 10−4; rs1877652 in PDE2A, p = 8 × 10−4) although non-significant after Bonferroni correction.Conclusion: Our results suggest that genes implicated in the signaling pathways linked to G protein-coupled receptors participate to genetic susceptibility to ICDs in PD.

Published
2020
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4. PAK3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migration

Author

Kévin Duarte, Solveig Heide, Sandrine Poëa-Guyon, Véronique Rousseau, Christel Depienne, Agnès Rastetter, Caroline Nava, Tania Attié-Bitach, Ferechté Razavi, Jelena Martinovic, Marie Laure Moutard, Jacqueline Cherfils, Cyril Mignot, Delphine Héron, and Jean-Vianney Barnier

Subjects
Corpus callosum agenesis (CCA), Cell adhesion, Cell migration, Cell spreading, Intellectual disability, Kinase, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Corpus callosum agenesis (CCA) is a brain malformation associated with a wide clinical spectrum including intellectual disability (ID) and an etiopathological complexity. We identified a novel missense G424R mutation in the X-linked p21-activated kinase 3 (PAK3) gene in a boy presenting with severe ID, microcephaly and CCA and his fetal sibling with CCA and severe hydrocephaly. PAK3 kinase is known to control synaptic plasticity and dendritic spine dynamics but its implication is less characterized in brain ontogenesis. In order to identify developmental functions of PAK3 impacted by mutations responsible for CCA, we compared the biochemical and biological effects of three PAK3 mutations localized in the catalytic domain. These mutations include two “severe” G424R and K389N variants (responsible for severe ID and CCA) and the “mild” A365E variant (responsible for nonsyndromic mild ID). Whereas they suppressed kinase activity, only the two severe variants displayed normal protein stability. Furthermore, they increased interactions between PAK3 and the guanine exchange factor αPIX/ARHGEF6, disturbed adhesion point dynamics and cell spreading, and severely impacted cell migration. Our findings highlight new molecular defects associated with mutations responsible for severe clinical phenotypes with developmental brain defects.

Published
2020
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5. Spatacsin and spastizin act in the same pathway required for proper spinal motor neuron axon outgrowth in zebrafish

Author

Elodie Martin, Constantin Yanicostas, Agnès Rastetter, Seyedeh Maryam Alavi Naini, Alissia Maouedj, Edor Kabashi, Sophie Rivaud-Péchoux, Alexis Brice, Giovanni Stevanin, and Nadia Soussi-Yanicostas

Subjects
Hereditary spastic paraplegia, SPG11, SPG15, Spatacsin, Spastizin, Zebrafish, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Hereditary spastic paraplegias (HSPs) are rare neurological conditions caused by degeneration of the long axons of the cerebrospinal tracts, leading to locomotor impairment and additional neurological symptoms. There are more than 40 different causative genes, 24 of which have been identified, including SPG11 and SPG15 mutated in complex clinical forms. Since the vast majority of the causative mutations lead to loss of function of the corresponding proteins, we made use of morpholino-oligonucleotide (MO)-mediated gene knock-down to generate zebrafish models of both SPG11 and SPG15 and determine how invalidation of the causative genes (zspg11 and zspg15) during development might contribute to the disease. Micro-injection of MOs targeting each gene caused locomotor impairment and abnormal branching of spinal cord motor neurons at the neuromuscular junction. More severe phenotypes with abnormal tail developments were also seen. Moreover, partial depletion of both proteins at sub-phenotypic levels resulted in the same phenotypes, suggesting for the first time, in vivo, a genetic interaction between these genes. In conclusion, the zebrafish orthologues of the SPG11 and SPG15 genes are important for proper development of the axons of spinal motor neurons and likely act in a common pathway to promote their proper path finding towards the neuromuscular junction.

Published
2012
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6. Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.

Author

Claire S Leblond, Caroline Nava, Anne Polge, Julie Gauthier, Guillaume Huguet, Serge Lumbroso, Fabienne Giuliano, Coline Stordeur, Christel Depienne, Kevin Mouzat, Dalila Pinto, Jennifer Howe, Nathalie Lemière, Christelle M Durand, Jessica Guibert, Elodie Ey, Roberto Toro, Hugo Peyre, Alexandre Mathieu, Frédérique Amsellem, Maria Rastam, I Carina Gillberg, Gudrun A Rappold, Richard Holt, Anthony P Monaco, Elena Maestrini, Pilar Galan, Delphine Heron, Aurélia Jacquette, Alexandra Afenjar, Agnès Rastetter, Alexis Brice, Françoise Devillard, Brigitte Assouline, Fanny Laffargue, James Lespinasse, Jean Chiesa, François Rivier, Dominique Bonneau, Beatrice Regnault, Diana Zelenika, Marc Delepine, Mark Lathrop, Damien Sanlaville, Caroline Schluth-Bolard, Patrick Edery, Laurence Perrin, Anne Claude Tabet, Michael J Schmeisser, Tobias M Boeckers, Mary Coleman, Daisuke Sato, Peter Szatmari, Stephen W Scherer, Guy A Rouleau, Catalina Betancur, Marion Leboyer, Christopher Gillberg, Richard Delorme, and Thomas Bourgeron

Subjects
Genetics, QH426-470
Abstract

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.

Published
2014
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7. SCN1A-related epilepsy with recessive inheritance: Two further families

Author

Julien Buratti, Isabelle Gourfinkel-An, Oriane Trouillard, Raffaella Moretti, Cyril Mignot, Delphine Bouteiller, Vincent des Portes, Patricia Moreau, Christel Depienne, Boris Keren, Agnès Rastetter, Lionel Arnaud, Joseph Toulouse, Caroline Nava, and Eric LeGuern

Subjects
Medizin, Epilepsies, Myoclonic, Biology, Asymptomatic, Seizures, Febrile, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Dravet syndrome, 030225 pediatrics, medicine, Humans, Missense mutation, Allele, Gene, Genetics, Seizure threshold, General Medicine, medicine.disease, NAV1.1 Voltage-Gated Sodium Channel, Phenotype, Mutation, Pediatrics, Perinatology and Child Health, Epilepsy syndromes, Neurology (clinical), medicine.symptom, Epileptic Syndromes, 030217 neurology & neurosurgery
Abstract

Background Variants in SCN1A gene, encoding the voltage-gated sodium channel Nav1.1, are associated with distinct epilepsy syndromes ranging from the relatively benign genetic epilepsy with febrile seizures plus (GEFS+) to Dravet syndrome, a severe developmental and epileptic encephalopathy (DEE). Most SCN1A pathogenic variants are heterozygous changes inherited in a dominant or de novo inheritance and many cause a loss-of-function of one allele. To date, recessive inheritance has been suggested in only two families with affected children harboring homozygous SCN1A missense variants while their heterozygous parents were asymptomatic. The aim of this report is to describe two additional families in which affected individuals have biallelic SCN1A variants possibly explaining their phenotype. Methods and results We report two novel homozygous SCN1A missense variants in two patients from related parents. Both patients had fever-sensitive epilepsy beginning in the first months of life, followed by afebrile seizures, without severe cognitive impairment. Parents were asymptomatic. Next generation sequencing excluded a pathogenic variant in other genes involved in DEE. Estimation of pathogenicity scores by in-silico tools suggests that the impact of these SCN1A variants is less damaging than that of dominant pathogenic variants. Conclusion This study provides additional evidence that homozygous variants in SCN1A can cause GEFS+. This recessive inheritance would imply that hypomorphic variants may not necessarily cause epilepsy at the heterozygous state but may decrease the seizure threshold when combined.

Published
2021

8. Variants in the SK2 channel gene (KCNN2) lead to dominant neurodevelopmental movement disorders

Author

Sylvia A. Huisman, Fanny Mochel, Christel Depienne, Roberto Canitano, Sara S. Cathey, Kimberly Nugent, Konrad Platzer, Katherine L. Helbig, Deepali N. Shinde, Diego Lopergolo, Sandra Yang, Francesca Mari, Astrid S. Plomp, Berten Ceulemans, Sarah Weckhuysen, Agnès Rastetter, Nadja Ehmke, Julien Thevenon, Rami Abou Jamra, Elisa Benetti, Daniela del Gaudio, Elizabeth Roeder, Darrel Waggoner, Raymond J. Louie, Shawn Kacker, Manuel Holtgrewe, Alessandra Renieri, Susanne B. Kamphausen, Denise Horn, Ange Line Bruel, Carine Dalle, Quinten Waisfisz, Frank J. Kaiser, Golder N. Wilson, Human genetics, Pediatric surgery, Amsterdam Reproduction & Development (AR&D), Human Genetics, and Paediatric Genetics

Subjects
Male, 0301 basic medicine, Patch-Clamp Techniques, Movement disorders, Small-Conductance Calcium-Activated Potassium Channels, Medizin, Haploinsufficiency, 0302 clinical medicine, Missense mutation, Exome, Child, Frameshift Mutation, Exome sequencing, Genetics, Movement Disorders, Learning Disabilities, Middle Aged, Magnetic Resonance Imaging, White Matter, developmental delay, Child, Preschool, medicine.symptom, SK2 channel, KCNN2, ataxia, tremor, Adolescent, Adult, Cerebellar Ataxia, Electrophysiological Phenomena, Genetic Variation, Humans, Intellectual Disability, Mutation, Missense, Neurodevelopmental Disorders, Young Adult, Ataxia, Biology, Frameshift mutation, 03 medical and health sciences, medicine, Preschool, Cerebellar ataxia, 030104 developmental biology, Mutation, Neurology (clinical), Missense, 030217 neurology & neurosurgery
Abstract

KCNN2 encodes the small conductance calcium-activated potassium channel 2 (SK2). Rodent models with spontaneous Kcnn2 mutations show abnormal gait and locomotor activity, tremor and memory deficits, but human disorders related to KCNN2 variants are largely unknown. Using exome sequencing, we identified a de novo KCNN2 frameshift deletion in a patient with learning disabilities, cerebellar ataxia and white matter abnormalities on brain MRI. This discovery prompted us to collect data from nine additional patients with de novo KCNN2 variants (one nonsense, one splice site, six missense variants and one in-frame deletion) and one family with a missense variant inherited from the affected mother. We investigated the functional impact of six selected variants on SK2 channel function using the patch-clamp technique. All variants tested but one, which was reclassified to uncertain significance, led to a loss-of-function of SK2 channels. Patients with KCNN2 variants had motor and language developmental delay, intellectual disability often associated with early-onset movement disorders comprising cerebellar ataxia and/or extrapyramidal symptoms. Altogether, our findings provide evidence that heterozygous variants, likely causing a haploinsufficiency of the KCNN2 gene, lead to novel autosomal dominant neurodevelopmental movement disorders mirroring phenotypes previously described in rodents.

Published
2020

9. Systematic analysis and prediction of genes associated with disorders on chromosome X

Author

Elsa Leitão, Christopher Schröder, Ilaria Parenti, Carine Dalle, Agnès Rastetter, Theresa Kühnel, Alma Kuechler, Sabine Kaya, Bénédicte Gérard, Elise Schaefer, Caroline Nava, Nathalie Drouot, Camille Engel, Juliette Piard, Bénédicte Duban-Bedu, Laurent Villard, Alexander P.A. Stegmann, Els K. Vanhoutte, Job A.J Verdonshot, Frank J. Kaiser, Frédéric Tran Mau-Them, Marcello Scala, Pasquale Striano, Suzanna G.M. Frints, Emanuela Argilli, Elliott H. Sherr, Fikret Elder, Julien Buratti, Boris Keren, Cyril Mignot, Delphine Héron, Jean-Louis Mandel, Jozef Gecz, Vera M. Kalscheuer, Bernhard Horsthemke, Amélie Piton, and Christel Depienne

Abstract

Disease gene discovery on chromosome (chr) X is challenging owing to its unique modes of inheritance. We undertook a systematic analysis of human chrX genes. We observe a higher proportion of disorder-associated genes and an enrichment of genes involved in cognition, language, and seizures on chrX compared to autosomes. We analyze gene constraints, exon and promoter conservation, expression and paralogues, and report 127 genes sharing one or more attributes with known chrX disorder genes. Using a neural network trained to distinguish disease-associated from dispensable genes, we classify 235 genes, including 121 of the 127, as having high probability of being disease-associated. We provide evidence of an excess of variants in predicted genes in existing databases. Finally, we report damaging variants in CDK16 and TRPC5 in patients with intellectual disability or autism spectrum disorders. This study predicts large-scale gene-disease associations that could be used for prioritization of X-linked pathogenic variants.

Published
2022

10. Mutations in the KIF21B kinesin gene cause neurodevelopmental disorders through imbalanced canonical motor activity

Author

Petra J. G. Zwijnenburg, Kirsty McWalter, Sonal Mahida, Delphine Héron, Frédéric Saudou, Hélène Vitet, Anna Chassevent, José Rivera Alvarez, Carlos A. Bacino, Juliette D. Godin, Christel Thauvin-Robinet, Chantal Weber, Laure Asselin, Caroline Nava, Christelle Golzio, Neil A. Hanchard, Christel Depienne, Peggy Tilly, Camille S. Bonnet, Cyril Mignot, Gladys Zapata, Amy Dameron, Marjan M. Weiss, Solveig Heide, Laurence Faivre, Haley Streff, Agnès Rastetter, Kristin W. Barañano, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Référence des Déficiences Intellectuelles de Causes Rares, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire [Grenoble] (CHU), Baylor College of Medicine (BCM), Baylor University, Texas Children's Hospital [Houston, USA], Kennedy Krieger Institute [Baltimore], GeneDx [Gaithersburg, MD, USA], Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Université de Bourgogne (UB), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Boston Children's Hospital, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Vrije Universiteit Amsterdam [Amsterdam] (VU), and University of Duisburg-Essen

Subjects
Male, 0301 basic medicine, Microcephaly, Organogenesis, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Medizin, Kinesins, General Physics and Astronomy, medicine.disease_cause, Mice, 0302 clinical medicine, Neurodevelopmental disorder, Cell Movement, Gene duplication, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Missense mutation, lcsh:Science, Zebrafish, Cerebral Cortex, Neurons, Mutation, Multidisciplinary, Neurodevelopmental disorders, Gene Expression Regulation, Developmental, Organ Size, Pedigree, 3. Good health, Kinesin, Female, Haploinsufficiency, Science, Mutation, Missense, Motor Activity, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, Animals, Humans, RNA, Messenger, Cell Proliferation, Corpus Callosum Agenesis, General Chemistry, medicine.disease, Axons, HEK293 Cells, 030104 developmental biology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Neuronal development, lcsh:Q, Nerve Net, Neuroscience, 030217 neurology & neurosurgery
Abstract

KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynamics. We report three missense variants and one duplication in KIF21B in individuals with neurodevelopmental disorders associated with brain malformations, including corpus callosum agenesis (ACC) and microcephaly. We demonstrate, in vivo, that the expression of KIF21B missense variants specifically recapitulates patients’ neurodevelopmental abnormalities, including microcephaly and reduced intra- and inter-hemispheric connectivity. We establish that missense KIF21B variants impede neuronal migration through attenuation of kinesin autoinhibition leading to aberrant KIF21B motility activity. We also show that the ACC-related KIF21B variant independently perturbs axonal growth and ipsilateral axon branching through two distinct mechanisms, both leading to deregulation of canonical kinesin motor activity. The duplication introduces a premature termination codon leading to nonsense-mediated mRNA decay. Although we demonstrate that Kif21b haploinsufficiency leads to an impaired neuronal positioning, the duplication variant might not be pathogenic. Altogether, our data indicate that impaired KIF21B autoregulation and function play a critical role in the pathogenicity of human neurodevelopmental disorder., Kinesins regulate intracellular transport and microtubule dynamics. Here, the authors show that KIF21B variants in humans associate with corpus callosum agenesis and microcephaly. Using mice and zebrafish, they showed the cellular mechanisms altered by the missense KIF21B variants.

Published
2020

11. PAK3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migration

Author

Caroline Nava, Ferechté Razavi, Kevin Duarte, Jelena Martinovic, Jacqueline Cherfils, Jean-Vianney Barnier, Christel Depienne, Delphine Héron, Cyrille Mignot, Agnès Rastetter, Solveig Heide, Marie Laure Moutard, Tania Attié-Bitach, Véronique Rousseau, Sandrine Poëa-Guyon, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institute of Human Genetics, University Hospital Essen, Embryology and genetics of human malformation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de foetopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Unité fonctionnelle de Fœtopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Laboratoire de biologie et pharmacologie appliquée (LBPA), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), Institut des Neurosciences de Paris-Saclay (Neuro-PSI), Department of genetics, Reference Center for Intellectual Disabilities of Rare Causes, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Department of Pediatrics Neurology, Reference Center for Intellectual Disabilities of Rare Causes, CHU Pitié-Salpêtrière [APHP], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Barnier, Jean-Vianney, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, 0301 basic medicine, Microcephaly, Kinase, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Intellectual disability, Medizin, medicine.disease_cause, Severity of Illness Index, Protein Structure, Secondary, 0302 clinical medicine, Neurodevelopmental disorder, Cell Movement, Chlorocebus aethiops, Missense mutation, Child, Genetics, Mutation, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Cell migration, Phenotype, Pedigree, [SDV] Life Sciences [q-bio], Neurology, COS Cells, αPIX/ARHGEF6, macromolecular substances, Biology, lcsh:RC321-571, 03 medical and health sciences, medicine, Animals, Humans, Amino Acid Sequence, Kinase activity, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Corpus Callosum Agenesis, Cell spreading, Cell adhesion, medicine.disease, Corpus callosum agenesis (CCA), HEK293 Cells, 030104 developmental biology, p21-Activated Kinases, PAK3, Agenesis of Corpus Callosum, 030217 neurology & neurosurgery
Abstract

International audience; Corpus callosum agenesis (CCA) is a brain malformation associated with a wide clinical spectrum including intellectual disability (ID) and an etiopathological complexity. We identified a novel missense G424R mutation in the X-linked p21-activated kinase 3 (PAK3) gene in a boy presenting with severe ID, microcephaly and CCA and his fetal sibling with CCA and severe hydrocephaly. PAK3 kinase is known to control synaptic plasticity and dendritic spine dynamics but its implication is less characterized in brain ontogenesis. In order to identify developmental functions of PAK3 impacted by mutations responsible for CCA, we compared the biochemical and biological effects of three PAK3 mutations localized in the catalytic domain. These mutations include two "se-vere" G424R and K389N variants (responsible for severe ID and CCA) and the "mild" A365E variant (responsible for nonsyndromic mild ID). Whereas they suppressed kinase activity, only the two severe variants displayed normal protein stability. Furthermore, they increased interactions between PAK3 and the guanine exchange factor αPIX/ARHGEF6, disturbed adhesion point dynamics and cell spreading, and severely impacted cell migration. Our findings highlight new molecular defects associated with mutations responsible for severe clinical phenotypes with developmental brain defects.

Published
2020

12. HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond

Author

Shoji Ichikawa, Ilaria Rivolta, Anna Binda, Laurie S. Sadler, Sonia Figueiroa, Renzo Guerrini, Annick Laridon, Pasquale Striano, Katalin Sterbova, Bina Santoro, Petra Laššuthová, Maria Margherita Mancardi, Francesca Ragona, Anna Rosati, Fernando Kok, Laura Canafoglia, Daniele Frattini, Elena Freri, Christine Coubes, Davide Mei, Bobby P. C. Koeleman, Daniel Bauer, Carla Marini, Christel Depienne, Carlotta Spagnoli, Sophie Scheidecker, Carlo Fusco, Tiziana Granata, Barbara Castellotti, Eva H. Brilstra, Federico Melani, Cristina Garrido, Cinzia Gellera, A. Micheil Innes, Wilfrid Carré, Christèle Dubourg, Elena Parrini, Alessandro Porro, Caroline Nava, Maria Giardino, Sophie Julia, Manuela Santos, Yves Alembik, Eric LeGuern, Andrea Barbuti, Silvana Franceschetti, Federico Zara, Paul Kuentz, Raffaella Milanesi, Catherine Mercer, Carine Dalle, Julien Thevenon, Nicolas Deconinck, Agnès Rastetter, Laurent Pasquier, Kay Hamacher, Renske Oegema, Gerhard Thiel, Dario DiFrancesco, Tiziana Pisano, Chelsea Chambers, Jacopo C. DiFrancesco, Guillaume Smits, Katherine L. Helbig, Julie Soblet, Jana Neupauerová, Damien R Clark, Johannes R. Lemke, Radhika Dhamija, Anna Moroni, 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), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University Medical Center [Utrecht], 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], CHU Pontchaillou [Rennes], Les Hôpitaux Universitaires de Strasbourg (HUS), Children’s Hospital of Philadelphia (CHOP ), University Hospital Motol [Prague], University of Genoa (UNIGE), Université libre de Bruxelles (ULB), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Marini, C, Porro, A, Rastetter, A, Dalle, C, Rivolta, I, Bauer, D, Oegema, R, Nava, C, Parrini, E, Mei, D, Mercer, C, Dhamija, R, Chambers, C, Coubes, C, Thévenon, J, Kuentz, P, Julia, S, Pasquier, L, Dubourg, C, Carré, W, Rosati, A, Melani, F, Pisano, T, Giardino, M, Innes, A, Alembik, Y, Scheidecker, S, Santos, M, Figueiroa, S, Garrido, C, Fusco, C, Frattini, D, Spagnoli, C, Binda, A, Granata, T, Ragona, F, Freri, E, Franceschetti, S, Canafoglia, L, Castellotti, B, Gellera, C, Milanesi, R, Mancardi, M, Clark, D, Kok, F, Helbig, K, Ichikawa, S, Sadler, L, Neupauerová, J, Laššuthova, P, Šterbová, K, Laridon, A, Brilstra, E, Koeleman, B, Lemke, J, Zara, F, Striano, P, Soblet, J, Smits, G, Deconinck, N, Barbuti, A, Difrancesco, D, Leguern, E, Guerrini, R, Santoro, B, Hamacher, K, Thiel, G, Moroni, A, Di Francesco, J, and Depienne, C

Subjects
0301 basic medicine, Proband, Male, Models, Molecular, Potassium Channels, [SDV]Life Sciences [q-bio], Medizin, medicine.disease_cause, Epileptogenesis, Membrane Potentials, Epilepsy, 0302 clinical medicine, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Missense mutation, Child, Genetics, Mutation, Middle Aged, Phenotype, 3. Good health, Transmembrane domain, clinical spectrum, epilepsy, HCN1, intellectual disability, ion channel, Child, Preschool, Epilepsy, Generalized, Female, Spasms, Infantile, Adult, Adolescent, CHO Cells, Biology, 03 medical and health sciences, Young Adult, Cricetulus, medicine, Animals, Humans, Generalized epilepsy, Genetic Association Studies, Aged, Infant, medicine.disease, Electric Stimulation, 030104 developmental biology, Mutagenesis, Site-Directed, Neurology (clinical), 030217 neurology & neurosurgery
Abstract

International audience; Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: one adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.

Published
2018

13. Targeted versus untargeted omics — the CAFSA story

Author

Emmanuel Roze, Frédéric Sedel, Christel Depienne, Ron A. Wevers, Christophe Junot, Agnès Rastetter, Clément Frainay, Claude Jardel, Farid Ichou, F. Lamari, Maria del Mar Amador, Benoit Colsch, Fabien Jourdan, Fanny Mochel, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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), MedDay Pharmaceuticals, Métabolisme et Xénobiotiques (ToxAlim-MeX), ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT), Radboud University Medical Center [Nijmegen], Les Hôpitaux Universitaires de Strasbourg (HUS), French Ministry of Health (PHRC SPECTMET-II) [RCB 2010-A01395-34], Service de Pharmacologie et d'Immunoanalyse (SPI), Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), 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], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)

Subjects
0301 basic medicine, Male, Folate, DNA Mutational Analysis, 01 natural sciences, Mass Spectrometry, chemistry.chemical_compound, Exome, Genetics (clinical), Exome sequencing, Tetrahydrofolates, Cerebellar ataxia, Genomics, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, DNA Polymerase gamma, Cerebrospinal fluid, Female, medicine.symptom, medicine.drug, Adult, Mitochondrial disease, DNA, Mitochondrial, 03 medical and health sciences, Metabolomics, All institutes and research themes of the Radboud University Medical Center, Exome Sequencing, Genetics, medicine, Humans, Carnitine, business.industry, Siblings, 010401 analytical chemistry, medicine.disease, N-Acetylneuraminic Acid, Sialic acid, 0104 chemical sciences, 030104 developmental biology, Targeted mass spectrometry, chemistry, Case-Control Studies, Cancer research, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Background In 2009, untargeted metabolomics led to the delineation of a new clinico-biological entity called cerebellar ataxia with elevated cerebrospinal free sialic acid, or CAFSA. In order to elucidate CAFSA, we applied sequentially targeted and untargeted omic approaches. Methods and results First, we studied five of the six CAFSA patients initially described. Besides increased CSF free sialic acid concentrations, three patients presented with markedly decreased 5-methyltetrahydrofolate (5-MTHF) CSF concentrations. Exome sequencing identified a homozygous POLG mutation in two affected sisters, but failed to identify a causative gene in the three sporadic patients with high sialic acid but low 5-MTHF. Using targeted mass spectrometry, we confirmed that free sialic acid was increased in the CSF of a third known POLG-mutated patient. We then pursued pathophysiological analyses of CAFSA using mass spectrometry-based metabolomics on CSF from two sporadic CAFSA patients as well as 95 patients with an unexplained encephalopathy and 39 controls. This led to the identification of a common metabotype between the two initial CAFSA patients and three additional patients, including one patient with Kearns-Sayre syndrome. Metabolites of the CSF metabotype were positioned in a reconstruction of the human metabolic network, which highlighted the proximity of the metabotype with acetyl-CoA and carnitine, two key metabolites regulating mitochondrial energy homeostasis. Conclusion Our genetic and metabolomics analyses suggest that CAFSA is a heterogeneous entity related to mitochondrial DNA alterations either through POLG mutations or a mechanism similar to what is observed in Kearns-Sayre syndrome.

Published
2018

14. Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance

Author

Amélie Piton, Melanie Bahlo, Paul J. Lockhart, Vesna Lukic, Caroline Nava, David J. Amor, Pierre Bitoun, Vicki Anderson, Fabien Lesne, Greta Gillies, Amanda G. Wood, Justine Guegan, Gail Robinson, Catherine Garel, Alexis Brice, Sarah E.M. Stephenson, Guy A. Rouleau, Aurélie Méneret, Delphine Héron, Kate Pope, Solveig Heide, Cyril Mignot, Emmanuel Roze, Angélique Quartier, Jean-Louis Mandel, Annalisa Paolino, Quentin Welniarz, Sylvie Odent, Florence Riant, George McGillivray, Linda J. Richards, Ilan Gobius, Elliott H. Sherr, Tania Attié-Bitach, Charles A. Galea, Timothy J. Edwards, Myriam Srour, Megan Spencer-Smith, Oriane Trouillard, Laura Morcom, Boris Keren, Christel Depienne, Marie Laure Moutard, Anne Faudet, Richard J. Leventer, Alissandra McIlroy, Agnès Rastetter, Thierry Billette de Villemeur, Simone Mandelstam, Jens Bunt, Martin B. Delatycki, Rick M. Tankard, Ashley P L Marsh, CHU Pitié-Salpêtrière [APHP], Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], CHU Trousseau [APHP], Service de Pédiatrie [Jean Verdier], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Service de Radiologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Institut de Génétique et Développement de Rennes (IGDR), 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 ), Service de génétique clinique [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Montreal Neurological Hospital, McGill University Health Center [Montreal] (MUHC), CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Diagnostic Génétique, CHU Strasbourg-Hopital Civil, Service des Maladies du Système Nerveux [CHU Pitié-Salpêtrière], Laboratoire de Génétique Moléculaire [CHRU Strasbourg], CHRU Strasbourg, Bioinformatics division, The Walter & Eliza Hall Institute of Medical Research, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France (CdF (institution)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Référence des Déficiences Intellectuelles de Causes Rares, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme ( GRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut de Génétique et de Biologie Moléculaire et Cellulaire ( IGBMC ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris 13 ( UP13 ) -Hôpital Jean Verdier, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Institut de Génétique et Développement de Rennes ( IGDR ), 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 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Sud, Neuroscience Paris Seine ( NPS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), McGill University Health Center [Montreal, Canada] ( MUHC ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Neuroprotection du Cerveau en Développement ( PROTECT ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], 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 Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), and 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)-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)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, 0301 basic medicine, Developmental Disabilities, Penetrance, Receptors, Cell Surface, Biology, Nervous System Malformations, Corpus callosum, medicine.disease_cause, Mirror movements, Article, Corpus Callosum, 03 medical and health sciences, 0302 clinical medicine, Neural Stem Cells, Netrin, Intellectual disability, Genetics, medicine, Humans, Abnormalities, Multiple, Family, 10. No inequality, Agenesis of the corpus callosum, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Tumor Suppressor Proteins, Brain, DCC Receptor, medicine.disease, Phenotype, 030104 developmental biology, nervous system, Female, Agenesis of Corpus Callosum, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, 030217 neurology & neurosurgery
Abstract

International audience; Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.

Published
2017

15. DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome

Author

Gail Robinson, Saumya Shekhar Jamuar, Elizabeth C. Engle, Helen M. Cooper, Guy A. Rouleau, Ashley P L Marsh, Christel Depienne, Thierry Billette de Villemeur, Linda J. Richards, Elliott H. Sherr, Richard J. Leventer, Delphine Héron, Agnès Rastetter, Marie-Laure Moutard, Charles A. Galea, Oriane Trouillard, Paul J. Lockhart, Timothy W. Yu, Megan Spencer-Smith, Emmanuel Roze, Timothy J. Edwards, Aurélie Méneret, Caroline Nava, Christopher A. Walsh, Murdoch Children's Research Institute (MCRI), University of Melbourne, Queensland Brain Institute, University of Queensland [Brisbane], Monash University [Parkville, VIC, Australie], Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Massachusetts Institute of Technology (MIT), KK Women's and Children's Hospital [Singapore], Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC), McGill University Health Center [Montreal] (MUHC), McGill University = Université McGill [Montréal, Canada], Monash University [Clayton], Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), UCSF Benioff Children's Hospital Oakland, University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Les Hôpitaux Universitaires de Strasbourg (HUS)

Subjects
0301 basic medicine, Models, Molecular, Deleted in Colorectal Cancer, Protein Conformation, NTN1, Biology, mirror movements, medicine.disease_cause, Germline, Article, 03 medical and health sciences, Protein Domains, Netrin, Databases, Genetic, Genetics, medicine, Missense mutation, Humans, Abnormalities, Multiple, Amino Acid Sequence, Agenesis of the corpus callosum, ACC, Genetics (clinical), Conserved Sequence, Genetic Association Studies, DCC, developmental split brain syndrome, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Binding Sites, axon guidance, fungi, Anatomy, Syndrome, Netrin-1, medicine.disease, Phenotype, Magnetic Resonance Imaging, 030104 developmental biology, Genes, DCC, horizontal gaze palsy with progressive scoliosis, Axon guidance, agenesis of the corpus callosum, Agenesis of Corpus Callosum, mutation, Protein Binding
Abstract

The deleted in colorectal cancer (DCC) gene encodes the netrin-1 receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum, or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome. Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed Netrin-1 signaling. Here we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated agenesis of the corpus callosum and developmental split brain syndrome, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus specific LOVD (https://databases.lovd.nl/shared/genes/DCC).

Published
2017

16. Annonacin, a natural lipophilic mitochondrial complex I inhibitor, increases phosphorylation of tau in the brain of FTDP-17 transgenic mice

Author

Wolfgang H. Oertel, Bertrand Friguet, Gesine Respondek, Günter U. Höglinger, Matthias Höllerhage, Agathe Tarze, Stefanie Müssner, Mohamed Salama, Christel Depienne, Agnès Rastetter, Anderson de Andrade, Pierre Champy, Elizabeth Sumi Yamada, Guellaen, Georges, Experimental Neurology, Philipps University, Experimental Neuropathology Laboratory, University Hospital João de Barros Barreto-Federal University of Para - Universidade Federal do Pará - UFPA [Belém, Brazil] (UFPA), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Department of Neurology, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire de Biologie Cellulaire du vieillissement, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR83, Laboratoire de Pharmacognosie (BioCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Deutsche Forschungsgemeinschaft (HO2402/6-1, HO2402/8-1), the German Ministry of Education and Research (BMBF EF 10-54), the Centre National de la Recherche Scientifique (CNRS), a Marie Curie Incoming International Fellowship (21996 to E.S.Y.) and the German Academic Exchange Service (DAAD to A.C.F.d.A.)., University Hospital João de Barros Barreto-Federal University of Para - Universidade Federal do Para [Belem - Brésil], Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Intégrative (IFR-BI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Neurons, pharmacology [Enzyme Inhibitors], drug effects [Gene Expression Regulation], genetics [Gene Expression Regulation], drug effects [Microglia], MESH: Dose-Response Relationship, Drug, Mice, Lactones, chemistry.chemical_compound, 0302 clinical medicine, MESH: Animals, Phosphorylation, pharmacology [Furans], Enzyme Inhibitors, genetics [Arginine], Neurons, 0303 health sciences, Kinase, Neurodegeneration, neurodegeneration, MESH: Arginine, Tryptophan, Brain, MESH: Gene Expression Regulation, Mitochondria, MESH: tau Proteins, Cell biology, MESH: Microglia, Neurology, Biochemistry, MESH: Enzyme Inhibitors, drug effects [Brain], Microglia, genetics [Tryptophan], Tauopathy, Microtubule-Associated Proteins, MESH: Lactones, Genetically modified mouse, MESH: Mutation, MESH: Mice, Transgenic, MESH: Mitochondria, Annonacin, Mice, Transgenic, genetics [Mutation], MAPT protein, human, tau Proteins, Biology, Arginine, MESH: Brain, 03 medical and health sciences, drug effects [Phosphorylation], Developmental Neuroscience, MESH: Mice, Inbred C57BL, mental disorders, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Humans, drug effects [Neurons], [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, ddc:610, Mortality, genetics [Phosphorylation], Furans, MESH: Mice, MESH: Tryptophan, 030304 developmental biology, MESH: Humans, MESH: Mortality, MESH: Phosphorylation, Dose-Response Relationship, Drug, Cyclin-dependent kinase 5, tauopathy, MESH: Furans, metabolism [Microtubule-Associated Proteins], annonacin, metabolism [Mitochondria], medicine.disease, Mice, Inbred C57BL, MESH: Microtubule-Associated Proteins, genetics [tau Proteins], Somatodendritic compartment, Gene Expression Regulation, chemistry, environmental neurotoxin, metabolism [Brain], Mutation, pharmacology [Lactones], genetics [Mitochondria], microtubule-associated protein tau, 030217 neurology & neurosurgery
Abstract

International audience; Both genetic and environmental factors likely contribute to the neuropathology of tauopathies, but it remains unclear how specific genetic backgrounds affect the susceptibility towards environmental toxins. Mutations in the tau gene have been associated with familial tauopathies, while annonacin, a plant-derived mitochondrial inhibitor, has been implicated in an environmental form of tauopathy. We therefore determined whether there was a pathogenic synergy between annonacin exposure and the expression of the R406W-tau mutation in transgenic mice. We found that annonacin exposure caused an increase in the number of neurons with phosphorylated tau in the somatodendritic compartment in several brain areas in R406W(+/+) mice as opposed to mice that had only the endogenous mouse tau (R406W(-/-)). Western blot analysis demonstrated a concomitant increase in total tau protein without increase in tau mRNA, but reduced proteasomal proteolytic activity in R406W(+/+), but not R406W(-/-) mice, upon annonacin-treatment. Phosphorylated tau levels exceeded the increase in total tau protein, along with increased levels of different tau kinases, foremost a striking increase in the p25/p35 ratio, known to activate the tau kinase Cdk5. In summary, we observed a synergistic interaction between annonacin exposure and the presence of the R406W-tau mutation, which resulted in reduced degradation, increased phosphorylation and redistribution of neuronal tau.

Published
2014

17. Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

Author

Marion Leboyer, Didier Périsse, Anne Faudet, Eric Fonteneau, Delphine Héron, Cyril Mignot, David Cohen, Nathalie Dorison, Sandra Whalen, Aurélia Jacquette, Sandra Chantot-Bastaraud, Diane Doummar, Claire Amiet, Boris Keren, Jean-Pierre Siffroi, Claudine Laurent, Caroline Nava, Agnès Rastetter, Alexis Brice, Alexandra Afenjar, and Christel Depienne

Subjects
Cri-du-Chat Syndrome, Male, Proband, congenital, hereditary, and neonatal diseases and abnormalities, Candidate gene, medicine.medical_specialty, Adolescent, DNA Copy Number Variations, Genotype, endocrine system diseases, Trisomy, Biology, Polymorphism, Single Nucleotide, Article, Genetic linkage, mental disorders, Genetics, medicine, Humans, SNP, Copy-number variation, Child, Genetic Association Studies, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Chromosomes, Human, Pair 15, Comparative Genomic Hybridization, Infant, DNA Methylation, Human genetics, Child Development Disorders, Pervasive, Child, Preschool, Chromosomes, Human, Pair 5, Medical genetics, Female, Comparative genomic hybridization
Abstract

Copy number variants (CNVs) have repeatedly been found to cause or predispose to autism spectrum disorders (ASDs). For diagnostic purposes, we screened 194 individuals with ASDs for CNVs using Illumina SNP arrays. In several probands, we also analyzed candidate genes located in inherited deletions to unmask autosomal recessive variants. Three CNVs, a de novo triplication of chromosome 15q11-q12 of paternal origin, a deletion on chromosome 9p24 and a de novo 3q29 deletion, were identified as the cause of the disorder in one individual each. An autosomal recessive cause was considered possible in two patients: a homozygous 1p31.1 deletion encompassing PTGER3 and a deletion of the entire DOCK10 gene associated with a rare hemizygous missense variant. We also identified multiple private or recurrent CNVs, the majority of which were inherited from asymptomatic parents. Although highly penetrant CNVs or variants inherited in an autosomal recessive manner were detected in rare cases, our results mainly support the hypothesis that most CNVs contribute to ASDs in association with other CNVs or point variants located elsewhere in the genome. Identification of these genetic interactions in individuals with ASDs constitutes a formidable challenge.

Published
2013

18. ARID1B mutations are the major genetic cause of corpus callosum anomalies in patients with intellectual disability

Author

Alain Verloes, Caroline Alby, Cécile Masson, Caroline Nava, Aurélia Jacquette, Tania Attié-Bitach, Catherine Garel, Thierry Bienvenu, Anne Faudet, Cyril Mignot, Christine Bole-Feysot, Patrick Nitschké, Alexandra Afenjar, Fabien Lesne, Didier Lacombe, Diane Doummar, Solveig Heide, Delphine Héron, Agnès Rastetter, Christel Depienne, Thierry Billette, Lucile Boutaud, and Marie-Laure Moutard

Subjects
0301 basic medicine, Pediatrics, medicine.medical_specialty, Population, Corpus callosum, Corpus Callosum, 03 medical and health sciences, Intellectual Disability, Intellectual disability, medicine, Humans, Abnormalities, Multiple, Copy-number variation, education, Agenesis of the corpus callosum, Psychiatry, Letters to the Editor, Pathological, education.field_of_study, Genetic heterogeneity, medicine.disease, DNA-Binding Proteins, 030104 developmental biology, Mutation, Dysplastic corpus callosum, Neurology (clinical), Agenesis of Corpus Callosum, Psychology
Abstract

Sir, In their extensive review article in Brain , Edwards et al. (2014) presented physiological processes underlying the formation of the corpus callosum, as well as pathological conditions in mice and humans leading to agenesis of the corpus callosum (AgCC). They reviewed most human syndromes associated with AgCC and emphasized the great heterogeneity of known genetic causes of AgCC in humans by listing more than 70 single gene mutations and copy number variations (CNV), which altogether explain 30–45% of all cases. Most of these genetic anomalies are responsible for AgCC associated with other cerebral or extra-cerebral malformations and/or intellectual disability (ID). The association between AgCC and intellectual disability is further highlighted by the higher prevalence of AgCC in individuals with intellectual disability (2–3%) versus in the general population (0.025–0.02%) (Paul et al. , 2007; Sotiriadis and Makrydimas, 2012). Thereby, given the extreme genetic heterogeneity of intellectual disability (Deciphering Developmental Disorders Study, 2015) and the number of genes involved in the formation of the corpus callosum in humans, it is not surprising that genetic causes of syndromes associating AgCC and intellectual disability are so numerous. However, the prevalence of each of these genetic anomalies in individuals with this association is currently unknown. To improve our knowledge on genetic causes of AgCC with intellectual disability, we collected prospectively clinical and molecular data from 177 individuals with anomalies of the corpus callosum (ACC, comprising patients with AgCC, or with short corpus callosum or with dysplastic corpus callosum), and intellectual disability (or developmental delay for young children; ACC-ID) between 2009 and 2015. A clinical diagnosis, further confirmed by targeted sequencing of the corresponding gene, when possible, was made for 15 patients. Among these patients, one had a diagnosis of Coffin-Siris syndrome (CSS) and a mutation in ARID1B , the major gene for Coffin-Siris …

Published
2016

19. Reversible generalized dystonia and encephalopathy from thiamine transporter 2 deficiency

Author

Mercedes Serrano, Mónica Rebollo, Rafael Artuch, Jordi Muchart, Jose A. Obeso, Christel Depienne, Belén Pérez-Dueñas, Agnès Rastetter, Emilio Fernández-Alvarez, and Loreto Martorell

Subjects
Dystonia, medicine.medical_specialty, Encephalopathy, food and beverages, Striatum, Biology, medicine.disease, Endocrinology, Neurology, Internal medicine, SLC19A3, Basal ganglia, medicine, biology.protein, Thiamine, Neurology (clinical), human activities, Basal ganglia disease, Dystonic disorder
Abstract

Background: Thiamine transporter-2 deficiency, a condition resulting from mutations in the SLC19A3 gene, has been described in patients with subacute dystonia and striatal necrosis. The condition responds extremely well to treatment with biotin and has thus been named biotin-responsive basal ganglia disease. Recently, this deficiency has also been related to Wernicke's-like encephalopathy and atypical infantile spasms, showing heterogeneous responses to biotin and/or thiamine. Methods: Two Spanish siblings with a biotin-responsive basal ganglia disease phenotype and mutations in SLC19A3 presented with acute episodes of generalized dystonia, rigidity, and symmetrical lesions involving the striatum, midline nuclei of the thalami, and the cortex of cerebral hemispheres as shown by magnetic resonance imaging. Results: The clinical features resolved rapidly after thiamine administration. Conclusions: Despite the rarity of thiamine transporter–2 deficiency, it should be suspected in patients with acute dystonia and basal ganglia injury, as thiamine can halt disease evolution and prevent further episodes. © 2012 Movement Disorder Society

Published
2012

20. KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations

Author

Emeline Mundwiller, Bat-El Zimmerman, Israela Lerer, Hamid Azzedine, Gabor Gyapay, Stephan Klebe, Vincent Meyer, Wassila Carpentier, Alexander Lossos, Agnès Rastetter, Elodie Martin, Laurent Orlando, Alexis Brice, Moriya Gamliel, Cecilia Marelli, Alexandra Durr, Magdalena Nawara, Ruth Sheffer, Marion Gaussen, Delphine Bouteiller, Khalid H. El-Hachimi, Giovanni Stevanin, Adel Misk, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], 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)-Université Pierre et Marie Curie - Paris 6 (UPMC), Hadassah Hebrew University Medical Center [Jerusalem], Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Gestionnaire, Hal Sorbonne Université

Subjects
[SDV]Life Sciences [q-bio], Mutation, Missense, Kinesins, Genes, Recessive, Biology, medicine.disease_cause, Article, Genetic Heterogeneity, 03 medical and health sciences, 0302 clinical medicine, Genetic linkage, Hereditary sensory and autonomic neuropathy, Genetics, medicine, Humans, Missense mutation, Family, Genetics (clinical), 030304 developmental biology, KIF1A, 0303 health sciences, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Spastic Paraplegia, Hereditary, Genetic heterogeneity, Homozygote, Chromosome Mapping, medicine.disease, Pedigree, 3. Good health, [SDV] Life Sciences [q-bio], Phenotype, Chromosomes, Human, Pair 2, Chromosomal region, Candidate Gene Analysis, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract

International audience; The hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterised by progressive spasticity in the lower limbs. The nosology of autosomal recessive forms is complex as most mapped loci have been identified in only one or a few families and account for only a small percentage of patients. We used next-generation sequencing focused on the SPG30 chromosomal region on chromosome 2q37.3 in two patients from the original linked family. In addition, wide genome scan and candidate gene analysis were performed in a second family of Palestinian origin. We identified a single homozygous mutation, p.R350G, that was found to cosegregate with the disease in the SPG30 kindred and was absent in 970 control chromosomes while affecting a strongly conserved amino acid at the end of the motor domain of KIF1A. Homozygosity and linkage mapping followed by mutation screening of KIF1A allowed us to identify a second mutation, p.A255V, in the second family. Comparison of the clinical features with the nature of the mutations of all reported KIF1A families, including those reported recently with hereditary sensory and autonomic neuropathy, suggests phenotype-genotype correlations that may help to understand the mechanisms involved in motor neuron degeneration. We have shown that mutations in the KIF1A gene are responsible for SPG30 in two autosomal recessive HSP families. In published families, the nature of the KIF1A mutations seems to be of good predictor of the underlying phenotype and vice versa.

Published
2012

21. Hypomorphic variants of cationic amino acid transporter 3 in males with autism spectrum disorders

Author

Caroline, Nava, Johanna, Rupp, Jean-Paul, Boissel, Cyril, Mignot, Agnès, Rastetter, Claire, Amiet, Aurélia, Jacquette, Céline, Dupuits, Delphine, Bouteiller, Boris, Keren, Merle, Ruberg, Anne, Faudet, Diane, Doummar, Anne, Philippe, Didier, Périsse, Claudine, Laurent, Nicolas, Lebrun, Vincent, Guillemot, Jamel, Chelly, David, Cohen, Delphine, Héron, Alexis, Brice, Ellen I, Closs, Christel, Depienne, 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 [APHP]-Centre National de la Recherche Scientifique ( CNRS ), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Department of pharmacology, Johannes Gutemberg Universität Mainz, Service de neuropédiatrie [Trousseau], Centre de Référence des Déficiences Intellectuelles de Causes Rares, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme ( GRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Service de psychiatrie enfant et adolescent, CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre diagnostic autisme, CHU Pitié-Salpêtrière [APHP], Institut Cochin ( 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 ), iCONICS, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique ( CNRS ), Institut des Systèmes Intelligents et de Robotique ( ISIR ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), CHU Trousseau [APHP], Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Institut des Systèmes Intelligents et de Robotique (ISIR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), 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 psychiatrie enfant et adolescent [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Administateur, HAL Sorbonne Université

Subjects
Male, Exome sequencing, Chromosome X, Autism Spectrum Disorder, Molecular Sequence Data, Clinical Biochemistry, Molecular Conformation, Mutation, Missense, Loss of Heterozygosity, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biochemistry, Xenopus laevis, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Gene Frequency, Animals, Humans, Biotinylation, Amino Acid Sequence, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Child, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Chromosomes, Human, X, Epilepsy, Cell Membrane, Organic Chemistry, Brain, Autism spectrum disorders, Pedigree, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Oocytes, Oligogenism, Amino Acid Transport Systems, Basic, Original Article, Cationic amino acid transporter
Abstract

Cationic amino acid transporters (CATs) mediate the entry of L-type cationic amino acids (arginine, ornithine and lysine) into the cells including neurons. CAT-3, encoded by the SLC7A3 gene on chromosome X, is one of the three CATs present in the human genome, with selective expression in brain. SLC7A3 is highly intolerant to variation in humans, as attested by the low frequency of deleterious variants in available databases, but the impact on variants in this gene in humans remains undefined. In this study, we identified a missense variant in SLC7A3, encoding the CAT-3 cationic amino acid transporter, on chromosome X by exome sequencing in two brothers with autism spectrum disorder (ASD). We then sequenced the SLC7A3 coding sequence in 148 male patients with ASD and identified three additional rare missense variants in unrelated patients. Functional analyses of the mutant transporters showed that two of the four identified variants cause severe or moderate loss of CAT-3 function due to altered protein stability or abnormal trafficking to the plasma membrane. The patient with the most deleterious SLC7A3 variant had high-functioning autism and epilepsy, and also carries a de novo 16p11.2 duplication possibly contributing to his phenotype. This study shows that rare hypomorphic variants of SLC7A3 exist in male individuals and suggest that SLC7A3 variants possibly contribute to the etiology of ASD in male subjects in association with other genetic factors. Electronic supplementary material The online version of this article (doi:10.1007/s00726-015-2057-3) contains supplementary material, which is available to authorized users.

Published
2015

22. Clinical, chromosomal and molecular characterization of a cohort of 273 patients with agenesis of the corpus callosum

Author

Annick Toutain, Tania Attié-Bitach, Cyril Mignot, Delphine Héron, Anne Faudet, Vincent des Portes, Didier Lacombe, Catherine Garel, Sandra Whalen, Laurence Faivre, Thierry Billette de Villemeur, Sandra Chantot-Bastaraud, Boris Keren, Christel Depienne, Lucile Boutaud, Solveig Heide, Marie-Laure Moutard, Caroline Nava, Agnès Rastetter, and Alexandra Afenjar

Subjects
Pathology, medicine.medical_specialty, business.industry, Pediatrics, Perinatology and Child Health, Cohort, Medicine, Neurology (clinical), General Medicine, business, Agenesis of the corpus callosum, medicine.disease
Published
2017

23. Corpus callosum agenesis with clinically normal people caused by DCC mutations. Prenatal implication

Author

Cyril Mignot, T Billette de Villemeur, Solveig Heide, Catherine Garel, Delphine Héron, Alexandra Afenjar, Christel Depienne, E. Blondiaux, V. des Portes, Caroline Nava, M.-L. Moutard, Boris Keren, Stéphanie Valence, and Agnès Rastetter

Subjects
business.industry, Corpus Callosum Agenesis, Pediatrics, Perinatology and Child Health, Medicine, Neurology (clinical), General Medicine, Anatomy, Normal people, business
Published
2017

24. Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments

Author

Anne Claude Tabet, Françoise Devillard, Christelle M. Durand, Dominique Bonneau, Caroline Schluth-Bolard, Hugo Peyre, Frédérique Amsellem, Jennifer L. Howe, Brigitte Assouline, Laurence Perrin, Patrick Edery, Gudrun A. Rappold, Alexis Brice, Tobias M. Boeckers, Kevin Mouzat, Mary Coleman, Diana Zelenika, Guy A. Rouleau, Christel Depienne, Alexandra Afenjar, Pilar Galan, Peter Szatmari, Coline Stordeur, Fabienne Giuliano, Thomas Bourgeron, Delphine Héron, Anthony P. Monaco, Aurélia Jacquette, Marion Leboyer, Elena Maestrini, Roberto Toro, Anne Polge, Serge Lumbroso, Richard Delorme, Maria Råstam, François Rivier, Richard Holt, Stephen W. Scherer, Jessica Guibert, Elodie Ey, Dalila Pinto, Christopher Gillberg, Béatrice Regnault, Fanny Laffargue, Claire S. Leblond, Julie Gauthier, Nathalie Lemière, James Lespinasse, Alexandre Mathieu, Michael J. Schmeisser, Jean Chiesa, Agnès Rastetter, Marc Delepine, Catalina Betancur, I. Carina Gillberg, Daisuke Sato, Mark Lathrop, Caroline Nava, Damien Sanlaville, Guillaume Huguet, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), 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), Service de Biochimie, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Laboratoire de diagnotic moléculaire, CHU Sainte Justine [Montréal], Service de génétique médicale, Hôpital l'Archet, Service de Psychiatrie de l'Enfant et de l'Adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Departments of Psychiatry, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Seaver Autism Center-, The Mindich Child Health & Development Institute, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Laboratoire de sciences cognitives et psycholinguistique (LSCP), Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS), Fondation FondaMental [Créteil], Department of Clinical Sciences, Lund University [Lund], Gillberg Neuropsychiatry Centre [Göteborg, Sueden], Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU), Department of Molecular Human Genetics, Universität Heidelberg [Heidelberg] = Heidelberg University, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-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), CHU Trousseau [APHP], Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant, Unité Pédopsychiatrique et Neuropédiatrique de Diagnostic et d'Evaluation des Troubles Envahissants du Développement, Centre Alpin de DIagnostic Précoce de l'Autisme - CADIPA-Centre Hospitalier Alpes Isère, Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Département de Génétique Chromosomique, Bâtiment Hôtel Dieu - Centre Hospitalier de Chambéry, Laboratoire de Cytogénétique, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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 de Biochimie et Génétique, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Génotypage des Eucaryotes (Plate-Forme), Institut Pasteur [Paris] (IP), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut for Anatomy and Cell Biology, Universität Ulm - Ulm University [Ulm, Allemagne], Foundation for Autism Research, Center of Excellence in Neuroscience, CHU de Montréal, Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Institute of Child Health, University College of London [London] (UCL), This work was funded by the Institut Pasteur, CNRS, INSERM, AP-HP, University Paris Diderot, the Bettencourt-Schueller foundation, the Orange foundation, the FondaMental foundation, the Conny-Maeva foundation, the Cognacq-Jay foundation, the ANR (ANR-08-MNPS-037-01 - SynGen), Neuron- ERANET (EUHF-AUTISM), the DFG (BO1718/3-1, 4-1) and Baustein L.SBN.0081., Leblond CS, Nava C, Polge A, Gauthier J, Huguet G, Lumbroso S, Giuliano F, Stordeur C, Depienne C, Mouzat K, Pinto D, Howe J, Lemière N, Durand CM, Guibert J, Ey E, Toro R, Peyre H, Mathieu A, Amsellem F, Rastam M, Gillberg IC, Rappold GA, Holt R, Monaco AP, Maestrini E, Galan P, Heron D, Jacquette A, Afenjar A, Rastetter A, Brice A, Devillard F, Assouline B, Laffargue F, Lespinasse J, Chiesa J, Rivier F, Bonneau D, Regnault B, Zelenika D, Delepine M, Lathrop M, Sanlaville D, Schluth-Bolard C, Edery P, Perrin L, Tabet AC, Schmeisser MJ, Boeckers TM, Coleman M, Sato D, Szatmari P, Scherer SW, Rouleau GA, Betancur C, Leboyer M, Gillberg C, Delorme R, Bourgeron T, Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Universität Heidelberg [Heidelberg], University of Oxford [Oxford], Unité Fonctionnelle de Génétique Clinique [CHU Pitié Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pasteur [Paris], Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon (CRNL), and Betancur, Catalina

Subjects
Male, Cancer Research, [SDV.GEN] Life Sciences [q-bio]/Genetics, medicine.disease_cause, GENE DELETION, 0302 clinical medicine, Cognition, Intellectual disability, Child, Genetics (clinical), Genetics, Psychiatry, Neurons, 0303 health sciences, Mutation, SDV:GEN, META-ANALYSIS, Penetrance, Hypotonia, 3. Good health, SHANK2, Autism spectrum disorder, Female, medicine.symptom, Research Article, lcsh:QH426-470, DNA Copy Number Variations, Nerve Tissue Proteins, Biology, 03 medical and health sciences, Intellectual Disability, mental disorders, medicine, Humans, Clinical significance, AUTISM, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Biology and Life Sciences, Human Genetics, medicine.disease, lcsh:Genetics, Child Development Disorders, Pervasive, Case-Control Studies, Synapses, Autism, Cognition Disorders, 030217 neurology & neurosurgery
Abstract

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability—more than 1 in 50—warrant its consideration for mutation screening in clinical practice., Author Summary Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders. Mutations altering genes involved in the junction between brain cells have been repeatedly associated in ASD. For example, SHANK1, SHANK2 and SHANK3 emerged as one family of genes that are associated with ASD. However, little was known about the number of patients carrying these mutations and the clinical outcome. Here, we performed a new genetic screen of SHANK mutations and these results were analyzed in combination with those of the literature. In summary, SHANK mutations account for ∼1% of patients with ASD and were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. Given the high frequency and impact of SHANK3 mutations in individuals with ASD and intellectual disability—more than 1 in 50—this gene should be screened for mutations in clinical practice.

Published
2014

25. Cellular distribution and subcellular localization of spatacsin and spastizin, two proteins involved in hereditary spastic paraplegia

Author

Charles Duyckaerts, Aurélien Dauphin, Elodie Martin, Giovanni Stevanin, Paola S. Denora, Frédéric Darios, Reena Prity Murmu, Khalid Hamid El Hachimi, Agnès Rastetter, Alexis Brice, Marie-Paule Muriel, Typhaine Esteves, and José Carlos Fernandez

Subjects
Cytoplasm, Hereditary spastic paraplegia, Mitochondrion, Biology, Cellular and Molecular Neuroscience, Mice, Microtubule, Cell Line, Tumor, medicine, Animals, Humans, Molecular Biology, Cells, Cultured, Motor Neurons, Spastic Paraplegia, Hereditary, Endoplasmic reticulum, Neurodegeneration, Proteins, Cell Biology, Subcellular localization, medicine.disease, Phenotype, Cell biology, Rats, Carrier Proteins, Neuroscience
Abstract

Truncating mutations in the SPG11 and SPG15 genes cause complicated spastic paraplegia, severe neurological conditions due to loss of the functions of spatacsin and spastizin, respectively. We developed specific polyclonal anti-spatacsin (SPG11) and anti-spastizin (SPG15) antisera, which we then used to explore the intracellular and tissue localizations of these proteins. We observed expression of both proteins in human and rat central nervous system, which was particularly strong in cortical and spinal motor neurons as well as in retina. Both proteins were also expressed ubiquitously and strongly in embryos. In cultured cells, these two proteins had similar diffuse punctate, cytoplasmic and sometimes nuclear (spastizin) distributions. They partially co-localized with multiple organelles, particularly with protein-trafficking vesicles, endoplasmic reticulum and microtubules. Spastizin was also found at the mitochondria surface. This first study of the endogenous expression of spatacsin and spastizin shows similarities in their expression patterns that could account for their overlapping clinical phenotypes and involvement in a common protein complex.

Published
2011

26. Reversible generalized dystonia and encephalopathy from thiamine transporter 2 deficiency

Author

Mercedes, Serrano, Mónica, Rebollo, Christel, Depienne, Agnès, Rastetter, Emilio, Fernández-Álvarez, Jordi, Muchart, Loreto, Martorell, Rafael, Artuch, José A, Obeso, and Belén, Pérez-Dueñas

Subjects
Male, Alanine, Magnetic Resonance Spectroscopy, Adolescent, Siblings, Membrane Transport Proteins, Magnetic Resonance Imaging, Basal Ganglia, Choline, Basal Ganglia Diseases, Dystonic Disorders, Child, Preschool, Humans, Female
Abstract

Thiamine transporter-2 deficiency, a condition resulting from mutations in the SLC19A3 gene, has been described in patients with subacute dystonia and striatal necrosis. The condition responds extremely well to treatment with biotin and has thus been named biotin-responsive basal ganglia disease. Recently, this deficiency has also been related to Wernicke's-like encephalopathy and atypical infantile spasms, showing heterogeneous responses to biotin and/or thiamine.Two Spanish siblings with a biotin-responsive basal ganglia disease phenotype and mutations in SLC19A3 presented with acute episodes of generalized dystonia, rigidity, and symmetrical lesions involving the striatum, midline nuclei of the thalami, and the cortex of cerebral hemispheres as shown by magnetic resonance imaging.The clinical features resolved rapidly after thiamine administration.Despite the rarity of thiamine transporter-2 deficiency, it should be suspected in patients with acute dystonia and basal ganglia injury, as thiamine can halt disease evolution and prevent further episodes. © 2012 Movement Disorder Society.

Published
2011

27. Biotin-responsive basal ganglia disease in ethnic Europeans with novel SLC19A3 mutations

Author

Agnès Bellanger, Olivier Lyon-Caen, Rabab Debs, Damien Galanaud, Alexis Brice, Christel Depienne, Bertrand Degos, Frédéric Sedel, Boris Keren, Agnès Rastetter, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), 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), Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière (NEMESIS-CRICM), 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)-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), Pathology Department, VU University Medical Center [Amsterdam], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Service de Neuroradiologie [CHU Pitié-Salpêtrière]

Subjects
Adult, Genetic Markers, Male, Pathology, medicine.medical_specialty, Genotype, DNA Mutational Analysis, Encephalopathy, Biotin, Basal Ganglia, White People, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Basal Ganglia Diseases, Arts and Humanities (miscellaneous), Basal ganglia, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Humans, Medicine, Genetic Predisposition to Disease, Thiamine, Basal ganglia disease, 030304 developmental biology, Dystonia, 0303 health sciences, Portugal, biology, Brain Diseases, Metabolic, business.industry, Putamen, Membrane Transport Proteins, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Europe, Treatment Outcome, Mutation, Vitamin B Complex, SLC19A3, biology.protein, Female, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

International audience; OBJECTIVE: To report the first 2 European cases of biotin-responsive basal ganglia disease and novel SLC19A3 mutations. DESIGN: Case reports. SETTING: University hospital. Patients A 33-year-old man and his 29-year-old sister, both of Portuguese ancestry, presented with recurrent episodes of encephalopathy. Between episodes patients exhibited generalized dystonia, epilepsy, and bilateral hyperintensities of the caudate and putamen. MAIN OUTCOME MEASURES: Clinical and radiologic findings. RESULTS: Administration of high doses of biotin or of a combination of biotin and thiamine during encephalopathies resulted in spectacular clinical and radiologic improvement in both patients. Sequencing of the SLC19A3 disclosed 2 novel mutations, both of which created premature stop codons in the protein sequence of hTHTR2. CONCLUSION: This study demonstrates that biotin-responsive basal ganglia disease is a panethnic condition. A therapeutic trial with high doses of biotin and thiamine seems mandatory in every unexplained encephalopathy with bilateral lesions of putamen and caudate nuclei.

Published
2010

28. Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE

Author

Didier Périsse, Clement A. Gautier, Guillaume Huguet, Anne Faudet, Claudine Laurent, C Dupuits, Christopher Gillberg, Delphine Bouteiller, Cyril Mignot, Delphine Héron, Sandra Whalen, David Cohen, Mylène Gilleron, Marion Leboyer, Boris Keren, Thomas Bourgeron, Marion Gérard, Alexis Brice, C. Depienne, Alexandra Afenjar, Agnès Rastetter, Foudil Lamari, Richard Delorme, Aurélia Jacquette, Caroline Nava, S Caillet, and Bruno Leheup

Subjects
Adult, Male, Candidate gene, TMLHE, Nonsense mutation, Biology, medicine.disease_cause, Polymerase Chain Reaction, Mixed Function Oxygenases, Cohort Studies, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Genes, X-Linked, medicine, Humans, Missense mutation, Exome, Family, Sex Distribution, Child, Genetic Association Studies, Biological Psychiatry, X chromosome, 030304 developmental biology, Genetics, Chromosomes, Human, X, 0303 health sciences, Mutation, carnitine, Autism spectrum disorders, medicine.disease, Psychiatry and Mental health, Child Development Disorders, Pervasive, male excess, Case-Control Studies, chromosome X, Autism, Original Article, next-generation sequencing, Female, 030217 neurology & neurosurgery
Abstract

The striking excess of affected males in autism spectrum disorders (ASD) suggests that genes located on chromosome X contribute to the etiology of these disorders. To identify new X-linked genes associated with ASD, we analyzed the entire chromosome X exome by next-generation sequencing in 12 unrelated families with two affected males. Thirty-six possibly deleterious variants in 33 candidate genes were found, including PHF8 and HUWE1, previously implicated in intellectual disability (ID). A nonsense mutation in TMLHE, which encodes the ɛ-N-trimethyllysine hydroxylase catalyzing the first step of carnitine biosynthesis, was identified in two brothers with autism and ID. By screening the TMLHE coding sequence in 501 male patients with ASD, we identified two additional missense substitutions not found in controls and not reported in databases. Functional analyses confirmed that the mutations were associated with a loss-of-function and led to an increase in trimethyllysine, the precursor of carnitine biosynthesis, in the plasma of patients. This study supports the hypothesis that rare variants on the X chromosome are involved in the etiology of ASD and contribute to the sex-ratio disequilibrium.

Published
2012

29. Callosal agenesis and congenital mirror movements : outcomes associated with DCC mutations

Author

Emmanuelle Lacaze, Gail Robinson, Jacquelyn L. Knight, Christel Depienne, Delphine Héron, Richard J. Leventer, Paul J. Lockhart, Megan Spencer-Smith, Linda J. Richards, Monash University [Melbourne], Murdoch Children's Research Institute (MCRI), University of Queensland [Brisbane], Institut des Nanosciences de Paris (INSP), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Duisburg-Essen, University of Melbourne, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Royal Alexandra Children's Hospital, Irc5 Consortium: Amelia Ceslis, Emily Gibson, Kim Giraudat, Alissandra McIlroy, Lynn K Paul, Vanessa Siffredi, Melanie Bahlo, Megan Barker, Eleonore Blondiaux, Timothy J Edwards, Catherine Garel, Solveig Heide, Boris Keren, Simone A Mandelstam, Ashley Pl Marsh, George McGillivray, Cyril Mignot, Marie-Laure Moutard, Caroline Nava, Kate Pope, Agnès Rastetter, Sarah Em Stephenson, Stéphanie Valence, Thierry Billette de Villemeur, Amanda Wood, Vicki Anderson, Elliott H Sherr, and univOAK, Archive ouverte

Subjects
Adult, Male, 030506 rehabilitation, Adolescent, Deleted in Colorectal Cancer, Medizin, [SDV.GEN] Life Sciences [q-bio]/Genetics, Neuropsychological Tests, Mirror movements, Cohort Studies, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Developmental Neuroscience, Neuroimaging, medicine, Humans, Young adult, Child, Agenesis of the corpus callosum, Callosal agenesis, [SDV.GEN]Life Sciences [q-bio]/Genetics, Movement Disorders, medicine.diagnostic_test, business.industry, Neuropsychology, Magnetic resonance imaging, Middle Aged, DCC Receptor, Prognosis, medicine.disease, Magnetic Resonance Imaging, nervous system, Mutation, Pediatrics, Perinatology and Child Health, Female, Neurology (clinical), Agenesis of Corpus Callosum, 0305 other medical science, business, Neuroscience, 030217 neurology & neurosurgery
Abstract

Pathogenic variants in the gene encoding deleted in colorectal cancer (DCC) are the first genetic cause of isolated agenesis of the corpus callosum (ACC). Here we present the detailed neurological, brain magnetic resonance imaging (MRI), and neuropsychological characteristics of 12 individuals from three families with pathogenic variants in DCC (aged 8-50y), who showed ACC and mirror movements (n=5), mirror movements only (n=2), ACC only (n=3), or neither ACC nor mirror movements (n=2). There was heterogeneity in the neurological and neuroimaging features on brain MRI, and performance across neuropsychological domains ranged from extremely low (impaired) to within normal limits (average). Our findings show that ACC and/or mirror movements are associated with low functioning in select neuropsychological domains and a DCC pathogenic variant alone is not sufficient to explain the disability. WHAT THIS PAPER ADDS: Neuropsychological impairment severity is related to presence of mirror movements and/or agenesis of the corpus callosum. A DCC pathogenic variant in isolation is associated with the best prognosis.

Published
2020

30. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Author

Florian R. T., Kraft F., Leitao E., Kaya S., Klebe S., Magnin E., van Rootselaar A. -F., Buratti J., Kuhnel T., Schroder C., Giesselmann S., Tschernoster N., Altmueller J., Lamiral A., Keren B., Nava C., Bouteiller D., Forlani S., Jornea L., Kubica R., Ye T., Plassard D., Jost B., Meyer V., Deleuze J. -F., Delpu Y., Avarello M. D. M., Vijfhuizen L. S., Rudolf G., Hirsch E., Kroes T., Reif P. S., Rosenow F., Ganos C., Vidailhet M., Thivard L., Mathieu A., Bourgeron T., Kurth I., Rafehi H., Steenpass L., Horsthemke B., Berkovic S. F., Bisulli F., Brancati F., Canafoglia L., Casari G., Guerrini R., Ishiura H., Licchetta L., Mei D., Pippucci T., Sadleir L., Scheffer I. E., Striano P., Tinuper P., Tsuji S., Zara F., LeGuern E., Klein K. M., Labauge P., Bennett M. F., Bahlo M., Gecz J., Corbett M. A., Tijssen M. A. J., van den Maagdenberg A. M. J. M., Depienne C., Florian, R. T., Kraft, F., Leitao, E., Kaya, S., Klebe, S., Magnin, E., van Rootselaar, A. -F., Buratti, J., Kuhnel, T., Schroder, C., Giesselmann, S., Tschernoster, N., Altmueller, J., Lamiral, A., Keren, B., Nava, C., Bouteiller, D., Forlani, S., Jornea, L., Kubica, R., Ye, T., Plassard, D., Jost, B., Meyer, V., Deleuze, J. -F., Delpu, Y., Avarello, M. D. M., Vijfhuizen, L. S., Rudolf, G., Hirsch, E., Kroes, T., Reif, P. S., Rosenow, F., Ganos, C., Vidailhet, M., Thivard, L., Mathieu, A., Bourgeron, T., Kurth, I., Rafehi, H., Steenpass, L., Horsthemke, B., Berkovic, S. F., Bisulli, F., Brancati, F., Canafoglia, L., Casari, G., Guerrini, R., Ishiura, H., Licchetta, L., Mei, D., Pippucci, T., Sadleir, L., Scheffer, I. E., Striano, P., Tinuper, P., Tsuji, S., Zara, F., Leguern, E., Klein, K. M., Labauge, P., Bennett, M. F., Bahlo, M., Gecz, J., Corbett, M. A., Tijssen, M. A. J., van den Maagdenberg, A. M. J. M., Depienne, C., Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Amsterdam Neuroscience [Pays-Bas], Vrije Universiteit Amsterdam [Amsterdam] (VU)-University of Amsterdam [Amsterdam] (UvA)-VU University Medical Center [Amsterdam], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre for Molecular Medicine Cologne [Cologne] (CMMC), University Hospital of Cologne [Cologne], Cologne Center for Genomics [Cologne] (CCG), University of Cologne, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), genomic vision, Leiden University Medical Center (LUMC), Universiteit Leiden, Centre de référence des épilepsies rares [CHRU Strasbourg] (CRéER), Centre Hospitalier Régional Universitaire de Strasbourg (CHRU de Strasbourg), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, School of Biological Sciences [Adelaïde], University of Adelaide, Goethe-University Frankfurt am Main, Philipps Universität Marburg = Philipps University of Marburg, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Melbourne, Epilepsy Research Centre, University of Calgary, Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), South Australian Health and Medical Research Institute [ Adelaide] (SAHMRI), University Medical Center Groningen [Groningen] (UMCG), This study has been financially supported by three different grants from the Fondation Maladies rares to C.D. (2009, 2010, 2016), Assistance Publique des Hôpitaux de Paris (APHP), INSERM, the 'Investissements d’Avenir' programme ANR-10-IAIHU-06 (IHU-A-ICM), University Duisburg-Essen and University Hospital Essen. M.B. was supported by an Australian National Health and Medical Research Council (NHMRC) Program Grant (GNT1054618) and an NHMRC Senior Research Fellowship (GNT1102971). This work was also supported by the Victorian Government’s Operational Infrastructure Support Program and the NHMRC Independent Research Institute Infrastructure Support Scheme (IRIISS). Laura Canafoglia: Member of the European Reference Network on Rare and Complex epilepsies, ERN EpiCARE., We thank the families for their participation in this study, Agnès Rastetter (ICM, Paris, France) for RNA extraction, and Emmanuelle Apartis (Hôpital Saint-Antoine, Paris, France) for electrophysiological assessment of Family 1. DNA extraction and cell culture of lymphoblasts have been performed at the DNA and cell bank of ICM (Paris, France). RNA-seq has been performed on the GenomEast platform of IGBMC, Illkirch, France. WGS has been performed by the Centre National de Recherche en Génomique Humaine (CNRGH) Institut de Biologie François Jacob, Evry, France. We thank Jean-Louis Mandel and Nicolas Charlet-Berguerand (IGBMC, Strasbourg, France), Cécile Cazeneuve (Hôpital Pitié-Salpêtrière, Paris, France), Charles Marcaillou (Integragen, Evry, France) and Isabel Silveira (Porto, Portugal) for valuable discussions., FAME consortium : Berkovic SF, Bisulli F, Brancati F, Canafoglia L, Casari G, Guerrini R, Ishiura H, Licchetta L, Mei D, Pippucci T, Sadleir L, Scheffer IE, Striano P, Tinuper P, Tsuji S, Zara F., Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), 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), Centre National de Recherche en Génomique Humaine (CNRGH), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), RWTH Aachen University, Universität Duisburg-Essen [Essen], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Philipps University of Marburg, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Rahel T. Florian, Florian Kraft, Elsa Leitão, Sabine Kaya, Stephan Klebe, Eloi Magnin, Anne-Fleur van Rootselaar, Julien Buratti, Theresa Kühnel, Christopher Schröder, Sebastian Giesselmann, Nikolai Tschernoster, Janine Altmueller, Anaide Lamiral, Boris Keren, Caroline Nava, Delphine Bouteiller, Sylvie Forlani, Ludmila Jornea, Regina Kubica, Tao Ye, Damien Plassard, Bernard Jost, Vincent Meyer, Jean-François Deleuze, Yannick Delpu, Mario D.M. Avarello, Lisanne S. Vijfhuizen, Gabrielle Rudolf, Edouard Hirsch, Thessa Kroes, Philipp S. Reif, Felix Rosenow, Christos Ganos, Marie Vidailhet, Lionel Thivard, Alexandre Mathieu, Thomas Bourgeron, Ingo Kurth, Haloom Rafehi, Laura Steenpass, Bernhard Horsthemke, FAME consortium, Eric LeGuern, Karl Martin Klein, Pierre Labauge, Mark F. Bennett, Melanie Bahlo, Jozef Gecz, Mark A. Corbett, Marina A.J. Tijssen, Arn M.J.M. van den Maagdenberg, Christel Depienne, Francesca Bisulli, Laura Licchetta, Paolo Tinuper, MATHIEU, Alexandre, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-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), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
Male, MESH: Introns, [SDV]Life Sciences [q-bio], Medizin, MESH: DNA Repeat Expansion, Epilepsies, Myoclonic, [SDV.GEN] Life Sciences [q-bio]/Genetics, MARCH6, expansion, MESH: Ubiquitin-Protein Ligases/genetics, MESH: Aged, MESH: Middle Aged, DNA Repeat Expansion, Neurodegenerative diseases, MESH: Epilepsies, Myoclonic, Chromosome Mapping, Middle Aged, MESH: Epilepsies, Myoclonic/genetics, Pedigree, MESH: Young Adult, Female, ddc:500, MESH: Membrane Proteins, Technology Platforms, Genomic instability, Adult, Adolescent, MESH: Pedigree, Ubiquitin-Protein Ligases, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Familial Adult Myoclonic Epilepsy type 3, Article, Young Adult, Humans, Aged, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Epilepsy, Membrane Proteins, MESH: Adult, MESH: Membrane Proteins/genetics, MESH: Ubiquitin-Protein Ligases, MESH: Male, Introns, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Chromosome Mapping, MESH: Female, Neurological disorders
Abstract

Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements., Familial cortical myoclonic tremor with epilepsy (FAME) is a slowly progressing cortical tremor mapping to various genomic loci, including intronic expansions in SAMD12 for FAME1. Here, Florian et al. describe mixed intronic TTTTA/TTTCA expansions of various lengths in the first intron of MARCH6 as a cause of FAME3.

Published
2019

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