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Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A Cause Malformations of Cortical Development and Microcephaly

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Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A Cause Malformations of Cortical Development and Microcephaly Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. Karine Poirier, Nicolas Lebrun, Loic Broix, Guoling Tian, Yoann Saillour, Cécile Boscheron, Elena Parrini, Stephanie Valence, Benjamin Saint Pierre, Madison Oger, et al. To cite this version: Karine Poirier, Nicolas Lebrun, Loic Broix, Guoling Tian, Yoann Saillour, et al.. Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and micro- cephaly.. Nature Genetics, Nature Publishing Group, 2013, 45 (6), pp.639-47. 10.1038/ng.2613. inserm-00838073 HAL Id: inserm-00838073 https://www.hal.inserm.fr/inserm-00838073 Submitted on 8 Oct 2013 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly Karine Poirier1,2, Nicolas Lebrun1,2, Loic Broix1,2*, Guoling Tian3*, Yoann Saillour1,2, Cécile Boscheron4, Elena Parrini5,6, Stephanie Valence1,2, Benjamin SaintPierre1,2, Madison Oger1,2, Didier Lacombe7, David Geneviève8, Elena Fontana9, Franscesca Darra9, Claude Cances10, Magalie Barth11,12, Dominique Bonneau11,12, Bernardo Dalla Bernadina9, Sylvie N’Guyen13, Cyril Gitiaux1,2,14,, Philippe Parent15, Vincent des Portes16, Jean Michel Pedespan17, Victoire Legrez18, Laetitia Castelnau-Ptakine1,2, Patrick Nitschke19, Thierry Hieu19, Cecile Masson19, Diana Zelenika20, Annie Andrieux4, Fiona Francis21,22, Renzo Guerrini5,6, Nicholas J. Cowan3, Nadia Bahi-Buisson1,2,14**, Jamel Chelly1,2** 1. Institut Cochin, Université Paris-Descartes, CNRS (UMR 8104), Paris, France, 2. Inserm, U1016, Paris, France, 3. Department of Biochemistry and Molecular Pharmacology, New York University Medical Center, New York, NY 10016 4. Institut des Neurosciences, Inserm, U836, Université Joseph Fourier – Grenoble 1, France 5. Pediatric Neurology Unit and Laboratories, Children's Hospital A. Meyer-University of Florence, Italy, 6. IRCCS Stella Maris Foundation. Pisa, Italy 7. Department of Medical Genetics, CHU Pellegrin, Bordeaux, France, 8. Department of Medical Genetics, Université Montpellier 1, INSERM U844, 34000 Montpellier, France, 9. UOC di Neuropsichiatria Infantile, Azienda Ospedaliera Univesritaria di Verona, Italy, 10. Département de Pédiatrie, CHU Toulouse, France, 11. INSERM: U694, Université d'Angers, CHU 4, Rue Larrey 49033 Angers Cedex, France, 12. Service de génétique CHU Angers, Angers, France, 13. Clinique Médicale Pédiatrique, CHU de Nantes, Nantes, France, 14. Unité de Neurologie Pédiatrique, Hôpital Necker Enfants Malades, Université Paris Descartes, France, 15. Service de Pédiatrie et Génétique Médicale , Brest, France, 16. Centre de référence déficiences intellectuelles de causes rares, CHU Lyon, Université Lyon1, L2C2 CNRS, Bron , France 17. Service de Pédiatrie, CHU Pellegrin, Bordeaux, France, 18. CHU Bicetre Service Neuropediatrie, Le Kremlin Bicetre, France 19. Bioinformatics plateform, Université Paris Descartes, Paris, France, 20. Centre National de Génotypage (CNG), Evry, France, 21. INSERM - Institut du Fer à Moulin, Paris, F75005, France, 22. Université Pierre et Marie Curie, Paris F75005, France, * and ** Equal contribution Corresponding authors Jamel Chelly Institut Cochin – Genetics and pathophysiology of neurodevelopmental disorders CHU Cochin, 24 Rue du Faubourg Saint Jacques 75014 Paris 33 1 44 41 24 10 [email protected] Nicholas J. Cowan Department of Biochemistry and Molecular Pharmacology New York University Langone Medical Center 550 First Avenue New York NY 10016. USA [email protected] 1 Abstract The genetic causes of malformations of cortical development (MCD) remain largely unknown. Here we report the discovery of multiple disease-causing missense mutations in TUBG1, DYNC1H1 and KIF2A, as well as a single germline mosaic mutation in KIF5C. We find a frequent recurrence of mutations in DYNC1H1, implying that this gene is a major locus implicated in unexplained MCD. The mutations in KIF5C, KIF2A and DYNC1H1 drastically affect ATP hydrolysis, productive protein folding or microtubule binding, while suppression of Tubg1 expression in vivo interferes with proper neuronal migration and expression of Tubg1 mutations in S. cerevisiae results in disruption of normal microtubule behaviour. Our data reinforce the importance of centrosome- and microtubule-related proteins in cortical development and strongly suggest that microtubule-dependent mitotic and post-mitotic processes are major contributors to the pathogenesis of MCD. 2 Introduction The formation of the complex architecture of the mammalian brain requires coordinated timing of proliferation, migration and layering, as well as differentiation of distinct neuronal populations1,2. Significant insights into these developmental processes have emerged through genetic and neurobiological investigations of the mechanisms underlying disorders of cortical development. These disorders include lissencephaly/pachygyria (LIS), polymicrogyria (PMG) and microcephaly3-7. Many are associated with severe intellectual disability and epilepsy, and have traditionally been classified based on which biological process (proliferation, migration and cortical organization) is likely to be affected5. Genetic studies in humans and mice have identified a spectrum of mutations in genes involved in an array of crucial processes that often disrupt the development of the cerebral cortex and can lead to severe cortical malformations. Aside from genes such as ARX and WDR62 (reviewed in5), the predominant importance of genes encoding cytoskeletal proteins has become evident. For example, mutations in DCX and LIS1, both of which encode proteins involved in microtubule homeostasis, are associated with a large spectrum of neuronal migration disorders (reviewed in3). More recently, new syndromes have been described that are associated with mutations in - or -tubulin encoding genes such as TUBA1A, TUBB2B, TUBB3 and TUBB5. These tubulin-related cortical dysgeneses are thought to involve a combination of abnormal neuronal proliferation, migration, differentiation and axonal guidance8-10. The vanishing boundaries between disorders of neuronal migration, cortical organization and proliferation have been highlighted by the recent identification of mutations in WDR62 and its implication in a large spectrum of malformations that includes pachygyria, lissencephaly, PMG, schizencephaly, hippocampal and cerebellar abnormalities11,12. These findings, together with genetic and functional data, support the hypothesis that MCD-related genes are involved at multiple developmental stages, and that proliferation and migration are genetically and functionally interdependent. Sporadic unexplained cases of MCD are by far the most common, and identification of causative mutations remains a challenging task, not least because many result from de novo mutations (reviewed in13). To extend the spectrum of genes involved in MCD, we used an exome sequencing approach and focused on variations in candidate genes encoding centrosomal and microtubule-related proteins. 3 Results Subgroups of patients with MCD analysed by whole exome sequencing We selected 16 patients with either lissencephaly/pachygyria (6 patients) or polymicrogyria (10 patients) associated with one of the following features: microcephaly (head circumferences more than 2-3 SD below the mean for age), dysgenesis of the cerebellum, brainstem or basal ganglia or agenesis/dysgenesis of the corpus callosum (Supplementary Table 1). Supplementary Figure 1 highlights the overall experimental workflow for detecting and prioritizing sequence variants and validation of the MCD-related genes detailed below. All families had a single affected member (sporadic cases), except one in which MCD was diagnosed in four individuals (P20, Fig. 1a). For all patients, mutations in known MCD genes (LIS1, DCX, TUBA1A, TUBB2B, TUBB3 and GPR56) and pathogenic CNVs had been previously excluded. We applied whole-exome sequencing methodology and, in line with previous studies14,15, identified around 21,500 variations affecting essential splicing site and coding regions for each patient. After application of variant filtering using available genomic databases (dbSNP, 1k genome, EVS and a local Paris Descartes Bioinformatics platform database) and exclusion of all variants found with a frequency greater than 1%, an average of 390 variants per patient was identified (Supplementary Table 2). A KIF5C germline mosaic mutation At first glance, in family P20 (Fig. 1a) containing 4 affected boys with severe MCD and microcephaly, the apparent transmission of the recurrent phenotype through the mother suggests the segregation in this family of an X-linked disorder. However, we found no linkage between the disease and a large set of X-linked markers (Supplementary Fig. 2a and 2b). Exclusion of the X chromosome and the unlikely autosomal recessive inheritance of the disorder (because of its occurrence even when the progenitor father was different) led us to consider a mosaic germline
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