Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations.
Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations.
复制标题
作者：
人类大脑皮质的发育是一个精心策划的过程，涉及神经祖细胞在室周生发区的诞生，以对称和不对称有丝分裂为特征的细胞增殖，然后有丝分裂后神经元迁移到其最终目的地。6个高度有序、功能特化的层。对指导这些复杂过程的分子机制的理解尚处于起步阶段，这主要是由于发现了导致皮质发育畸形（MCD）的罕见突变。在假定的孟德尔形式的MCD的疾病位点的映射已被阻碍了显着的基因座异质性，小的亲缘关系的大小和诊断分类，可能无法反映分子发病机制。在这里，我们证明了使用全外显子组测序，以克服这些障碍，确定隐性突变WDR62作为一个广泛的严重的大脑皮质畸形，包括小头畸形，厚骨症与皮质增厚以及发育不全的胼胝体的原因。一些WDR 62突变的患者有其他异常的证据，包括无脑回畸形，中脑畸形，多小脑回畸形，在一个例子中，小脑发育不全，所有特征传统上被认为是不同的实体。在小鼠和人类中，WDR 62转录物和蛋白质在脑室和脑室下区的神经祖细胞中富集。WDR 62在新皮层中的表达是短暂的，跨越胚胎神经发生的时期。与其他已知的小头畸形基因不同，WDR 62显然不与中心体相关，并且主要位于核内。这些发现统一了以前大脑皮层发育的不同方面，并强调了全外显子组测序在传统方法具有挑战性的环境中识别疾病位点的实用性。
The development of the human cerebral cortex is an orchestrated process involving the birth of neural progenitors in the peri-ventricular germinal zones, cell proliferation characterized by both symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in 6 highly ordered, functionally-specialized layers. 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 (MCD). Mapping of disease loci in putative Mendelian forms of MCD 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 WDR62 as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with WDR62 mutations had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mouse and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. WDR62 expression 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 utility of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging.
登录
查看更多内容
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
9.8
作者：
Kumar, Arun;Girimaji, Satish C.;Blanton, Susan H.
通讯作者：
Blanton, Susan H.
DOI：
10.1073/pnas.0806791105
发表时间：
2008-10-14
影响因子：
11.1
作者：
Kwan, Kenneth Y.;Lam, Mandy M. S.;Sestan, Nenad
通讯作者：
Sestan, Nenad
影响因子：
11.4
作者：
Thornton, Gemma K.;Woods, C. Geoffrey
通讯作者：
Woods, C. Geoffrey
影响因子：
7
作者：
Li, Heng;Ruan, Jue;Durbin, Richard
通讯作者：
Durbin, Richard