Genetic analysis of disheveled 2 and disheveled 3 in human neural tube defects.
Genetic analysis of disheveled 2 and disheveled 3 in human neural tube defects.
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DOI：
10.1007/s12031-012-9871-9
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发表时间：
2013-03
期刊：
影响因子：
--
通讯作者：
Capra V
中科院分区：
文献类型：
--
作者：
De Marco P;Merello E;Consales A;Piatelli G;Cama A;Kibar Z;Capra V
神经管缺陷是严重的畸形，影响1/1，000的活产。平面细胞极性通路控制神经管闭合，并在动物模型和人类队列中均涉及神经管缺陷的发病机制。在小鼠中，单独破坏Dvl 2（Dvl 2 −/−）或Dvl 2和Dvl 3（Dvl 2 −/−; Dvl 3 +/−，Dvl 2 +/−; Dvl 3 −/−）导致不完全的神经形成，表明Disheveled在神经管闭合中的作用。Disheveled是一种多功能蛋白，参与经典Wnt信号传导和非经典平面细胞极性途径。在这项研究中，我们分析了人类直系同源物DVL 2和DVL 3在473名神经管缺陷患者队列中的作用。在639个种族匹配的对照组中对罕见变异进行基因分型。我们确定了7个罕见的错义突变，在所有分析的对照中均不存在。在DVL 2中鉴定的这些突变中的两个，p.Tyr667Cys和p.Ala53Val，被预测为在计算机中是有害的。值得注意的是，在DVL 2的外显子15中的1-bp插入（c.1801_1802insG）预测导致蛋白质的截短被确定在一个复杂形式的尾部发育不全的患者。总之，我们证明了DVL 2基因的罕见变异作为神经管缺陷的危险因素的可能作用。本文的在线版本（doi：10.1007/s12031-012-9871-9）包含补充材料，可供授权用户使用。
Neural tube defects are severe malformations affecting 1/1,000 live births. The planar cell polarity pathway controls the neural tube closure and has been implicated in the pathogenesis of neural tube defects both in animal models and human cohorts. In mouse disruption of Dvl2 alone (Dvl2−/−) or Dvl2 and Dvl3 (Dvl2−/−; Dvl3+/−, Dvl2+/−; Dvl3−/−) results in incomplete neurulation, suggesting a role for Disheveled in neural tube closure. Disheveled is a multifunctional protein that is involved in both the canonical Wnt signaling and the noncanonical planar cell polarity pathway. In this study, we analyzed the role of the human orthologs DVL2 and DVL3 in a cohort of 473 patients with neural tube defects. Rare variants were genotyped in 639 ethnically matched controls. We identified seven rare missense mutations that were absent in all controls analyzed. Two of these mutations, p.Tyr667Cys and p.Ala53Val, identified in DVL2 were predicted to be detrimental in silico. Significantly, a 1-bp insertion (c.1801_1802insG) in exon 15 of DVL2 predicted to lead to the truncation of the protein was identified in a patient with a complex form of caudal agenesis. In summary, we demonstrate a possible role for rare variants in DVL2 gene as risk factors for neural tube defects. The online version of this article (doi:10.1007/s12031-012-9871-9) contains supplementary material, which is available to authorized users.
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