Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations

被引：367

作者：

Bilguvar, Kaya ^{[1
,2
,3
,4
]}

Ozturk, Ali Kemal ^{[1
,2
,3
,4
]}

Louvi, Angeliki ^{[1
,2
,3
,4
]}

Kwan, Kenneth Y. ^{[4
,5
]}

Choi, Murim ^{[1
,2
]}

Tatli, Burak ^{[6
]}

Yalnizoglu, Dilek ^{[7
]}

Tuysuz, Beyhan ^{[8
]}

Caglayan, Ahmet Okay ^{[9
]}

Gokben, Sarenur ^{[10
]}

Kaymakcalan, Hande ^{[11
]}

Barak, Tanyeri ^{[1
,2
,3
,4
]}

Bakircioglu, Mehmet ^{[1
,2
,3
,4
]}

Yasuno, Katsuhito ^{[1
,2
,3
,4
]}

Ho, Winson ^{[1
,2
,3
,4
]}

Sanders, Stephan ^{[1
,2
,12
,13
]}

Zhu, Ying ^{[4
,5
]}

Yilmaz, Sanem ^{[10
]}

Dincer, Alp ^{[14
]}

Johnson, Michele H. ^{[3
,15
,16
]}

Bronen, Richard A. ^{[3
,15
]}

Kocer, Naci ^{[17
]}

Per, Hueseyin ^{[18
]}

Mane, Shrikant ^{[1
,2
,19
]}

Pamir, Mehmet Necmettin ^{[20
]}

Yalcinkaya, Cengiz ^{[21
]}

Kumandas, Sefer ^{[18
]}

Topcu, Meral ^{[7
]}

Ozmen, Meral ^{[6
]}

Sestan, Nenad ^{[4
,5
]}

Lifton, Richard P. ^{[1
,2
,22
]}

State, Matthew W. ^{[1
,2
,12
,13
]}

Gunel, Murat ^{[1
,2
,3
,4
]}

机构：

[1] Yale Univ, Sch Med, Dept Genet, Ctr Human Genet & Genom, New Haven, CT 06510 USA

[2] Yale Univ, Sch Med, Program Neurogenet, New Haven, CT 06510 USA

[3] Yale Univ, Sch Med, Dept Neurosurg, New Haven, CT 06510 USA

[4] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT 06510 USA

[5] Yale Univ, Sch Med, Kavli Inst Neurosci, New Haven, CT 06510 USA

[6] Istanbul Univ, Istanbul Fac Med, Dept Pediat, Div Neurol, TR-34093 Istanbul, Turkey

[7] Hacettepe Univ, Sch Med, Dept Pediat, Div Neurol, TR-06100 Ankara, Turkey

[8] Istanbul Univ, Cerrahpasa Fac Med, Dept Pediat, Div Genet, TR-34098 Istanbul, Turkey

[9] Kayseri Educ & Res Hosp, Dept Med Genet, TR-38010 Kayseri, Turkey

[10] Ege Univ, Fac Med, Dept Pediat, Div Neurol, TR-35100 Izmir, Turkey

[11] Bahcesehir Univ, Fac Arts & Sci, TR-34353 Istanbul, Turkey

[12] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06510 USA

[13] Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 USA

[14] Acibadem Univ, Sch Med, Dept Radiol, TR-34742 Istanbul, Turkey

[15] Yale Univ, Sch Med, Dept Radiol, New Haven, CT 06510 USA

[16] Yale Univ, Sch Med, Dept Otolaryngol, New Haven, CT 06510 USA

[17] Istanbul Univ, Cerrahpasa Fac Med, Dept Radiol, TR-34098 Istanbul, Turkey

[18] Erciyes Univ, Sch Med, Dept Pediat, Div Neurol, TR-38039 Kayseri, Turkey

[19] Yale Univ, Sch Med, Yale Ctr Genome Anal, New Haven, CT 06510 USA

[20] Acibadem Univ, Sch Med, Dept Neurosurg, TR-34742 Istanbul, Turkey

[21] Istanbul Univ, Cerrahpasa Fac Med, Dept Neurol, Div Child Neurol, TR-34098 Istanbul, Turkey

[22] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA

来源：

NATURE | 2010年 / 467卷 / 7312期

基金：

美国国家卫生研究院;

关键词：

HUMAN CEREBRAL-CORTEX; GENETIC MALFORMATIONS; CLASSIFICATION; SLITRK1; CAPTURE;

D O I：

10.1038/nature09327

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：207 / U93

页数：5

共 25 条

[1] Sequence variants in SLITRK1 are associated with Tourette's syndrome [J].