Mutations in the COPII Vesicle Component Gene SEC24B are Associated with Human Neural Tube Defects
Mutations in the COPII Vesicle Component Gene SEC24B are Associated with Human Neural Tube Defects
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DOI：
10.1002/humu.22338
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发表时间：
2013-08
期刊：
影响因子：
3.9
通讯作者：
Xueyan Yang;Xiangda Zhou;Qing-Qing Wang-Qing;Hong Li;Ying Chen;Y. Lei;Xiao‐Hang Ma;Pan Kong;
中科院分区：
文献类型：
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作者：
Xueyan Yang;Xiangda Zhou;Qing-Qing Wang-Qing;Hong Li;Ying Chen;Y. Lei;Xiao‐Hang Ma;Pan Kong;
神经管缺陷（NTD）是一种严重的出生畸形，每1,000名活产婴儿中就有一名受到影响。最近，平面细胞极性（PCP）途径基因的突变已被牵连在NTDs的发病机制在小鼠模型和人类队列。小鼠模型表明，介导核心PCP基因Vangl 2作为COPII囊泡组分的ER至高尔基体转运的Sec 24 b的纯合破坏将导致颅脊柱裂。在这项研究中，我们发现了四个罕见的错义杂合SEC 24 B突变（p.Phe227Ser，p.Phe682Leu，p.Arg1248Gln和p.Ala1251Gly）在NTDs病例中，在所有对照中均不存在。其中p.Phe227Ser和p.Phe682Leu影响其蛋白质稳定性和与VANGL 2的物理相互作用。三种变体（p.Phe227Ser、p.Arg1248Gln和p.Ala1251Gly）被证明影响VANGL 2在培养细胞中的亚细胞定位。在斑马鱼中的进一步功能分析，包括过表达和剂量依赖性拯救研究，表明与野生型SEC 24 B相比，这四种突变均显示出功能丧失效应。我们的研究表明，SEC 24 B中的功能突变可能有助于人类NTD亚组的病因学，并进一步扩展了我们对PCP途径相关基因在人类NTD发病机制中作用的认识。
Neural tube defects (NTDs) are severe birth malformations that affect one in 1,000 live births. Recently, mutations in the planar cell polarity (PCP) pathway genes had been implicated in the pathogenesis of NTDs in both the mouse model and in human cohorts. Mouse models indicate that the homozygous disruption of Sec24b, which mediates the ER‐to‐Golgi transportation of the core PCP gene Vangl2 as a component of the COPII vesicle, will result in craniorachischisis. In this study, we found four rare missense heterozygous SEC24B mutations (p.Phe227Ser, p.Phe682Leu, p.Arg1248Gln, and p.Ala1251Gly) in NTDs cases that were absent in all controls. Among them, p.Phe227Ser and p.Phe682Leu affected its protein stability and physical interaction with VANGL2. Three variants (p.Phe227Ser, p.Arg1248Gln, and p.Ala1251Gly) were demonstrated to affect VANGL2 subcellular localization in cultured cells. Further functional analysis in the zebrafish including overexpression and dosage‐dependent rescue study suggested that these four mutations all displayed loss‐of‐function effects compared with wild‐type SEC24B. Our study demonstrated that functional mutations in SEC24B might contribute to the etiology of a subset of human NTDs and further expanded our knowledge of the role of PCP pathway‐related genes in the pathogenesis of human NTDs.