Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations
| Autor: | Tanyeri Barak, Ying Zhu, Mehmet Bakırcıoğlu, Shrikant Mane, Richard P. Lifton, Hüseyin Per, Mehmet Necmettin Pamir, Nenad Sestan, Sarenur Gökben, Murat Gunel, Winson S. Ho, Sefer Kumandaş, Katsuhito Yasuno, Ali K. Ozturk, Matthew W. State, Dilek Yalnizoglu, Sanem Yilmaz, Michele H. Johnson, Beyhan Tüysüz, Angeliki Louvi, Richard A. Bronen, Stephen Sanders, Ahmet Okay Caglayan, Cengiz Yalcinkaya, Murim Choi, Burak Tatlı, Meral Topçu, Hande Kaymakçalan, Kenneth Y. Kwan, Meral Özmen, Kaya Bilguvar, Alp Dinçer, Naci Kocer |
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| Přispěvatelé: | Acibadem University Dspace, Çocuk Sağlığı ve Hastalıkları, Ege Üniversitesi |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Male
Microcephaly DNA Mutational Analysis Cell Cycle Proteins Mice 0302 clinical medicine Locus heterogeneity Polymicrogyria 2.1 Biological and endogenous factors Aetiology Exome sequencing Genetics Pediatric 0303 health sciences Brain Diseases Multidisciplinary Neocortex Brain 3. Good health Pedigree medicine.anatomical_structure Cerebral cortex Neurological Female General Science & Technology Intellectual and Developmental Disabilities (IDD) Molecular Sequence Data Lissencephaly Genes Recessive Nerve Tissue Proteins Biology 03 medical and health sciences Rare Diseases medicine Recessive Animals Humans 030304 developmental biology Base Sequence Pachygyria Human Genome Neurosciences medicine.disease Stem Cell Research Brain Disorders Genes Mutation Congenital Structural Anomalies 030217 neurology & neurosurgery |
| Zdroj: | Nature, vol 467, iss 7312 |
| Popis: | WOS: 000281616300034 PubMed ID: 20729831 The development of the human cerebral cortex is an orchestrated process involving the generation of neural progenitors in the periventricular germinal zones, cell proliferation characterized by symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in six highly ordered, functionally specialized layers(1,2). An understanding of the molecular mechanisms guiding these intricate processes is in its infancy, substantially driven by the discovery of rare mutations that cause malformations of cortical development(3-6). Mapping of disease loci in putative Mendelian forms of malformations of cortical development has been hindered by marked locus heterogeneity, small kindred sizes and diagnostic classifications that may not reflect molecular pathogenesis. Here we demonstrate the use of whole-exome sequencing to overcome these obstacles by identifying recessive mutations in WD repeat domain 62 (WDR62) as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with mutations in WDR62 had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mice and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. Expression of WDR62 in the neocortex is transient, spanning the period of embryonic neurogenesis. Unlike other known microcephaly genes, WDR62 does not apparently associate with centrosomes and is predominantly nuclear in localization. These findings unify previously disparate aspects of cerebral cortical development and highlight the use of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging. Yale Program on Neurogenetics; Yale Center for Human Genetics and Genomics; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [RC2 NS070477, UL1 RR024139NIH, UO1MH081896]; National Institutes of Health Neuroscience Microarray ConsortiumUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U24 NS051869-02S1] We are indebted to the patients and families who have contributed to this study. We thank J. Noonan for expert advice and C. Camputaro for her help with three-dimensional reconstruction of the magnetic resonance images. This study was supported by the Yale Program on Neurogenetics, the Yale Center for Human Genetics and Genomics, and National Institutes of Health grants RC2 NS070477 (to M.G.), UL1 RR024139NIH (Yale Clinical and Translational Science Award) and UO1MH081896 (to N.S.). SNP genotyping was supported in part by a National Institutes of Health Neuroscience Microarray Consortium award U24 NS051869-02S1 (to S.M.). R.P.L. is an investigator of the Howard Hughes Medical Institute. |
| Databáze: | OpenAIRE |
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