Extensive studies that have sought causative mutation(s) for neural tube defects (NTDs) have yielded limited positive findings to date. One possible reason for this is that many studies have been confined to analyses of germline mutations and so may have missed other, non-germline mutations in NTD cases. We hypothesize that somatic mutations of planar polarity pathway (PCP) genes may play a role in the development of NTDs. Torrent™ Personal Genome Machine™ (PGM) sequencing was designed for selected PCP genes in paired DNA samples extracted from the tissues of lesion sites and umbilical cord from 48 cases. Sanger sequencing was used to validate the detected mutations. The source and distribution of the validated mutations in tissues from different germ layers were investigated. Subcellular location, western blotting, and luciferase assays were performed to better understand the effects of the mutations on protein localization, protein level, and pathway signaling. ix somatic mutations were identified and validated, which showed diverse distributions in different tissues. Three somatic mutations were novel/rare: CELSR1 p.Gln2125His, FZD6 p.Gln88Glu, and VANGL1 p.Arg374His. FZD6 p.Gln88Glu caused mislocalization of its protein from the cytoplasm to the nucleus, and disrupted the colocalization of CELSR1 and FZD6. This mutation affected non-canonical WNT signaling in luciferase assays. VANGL1 p.Arg374His impaired the co-localization of CELSR1 and VANGL1, increased the protein levels of VANGL1, and influenced cell migration. In all, 7/48 (14.5%) of the studied NTD cases contained somatic PCP mutations. Somatic mutations in PCP genes (e.g., FZD6 and VANGL1) are associated with human NTDs, and they may occur in different stages and regions during embryonic development, resulting in a varied distribution in fetal tissues/organs.

中文翻译：

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具有神经管缺陷的人类胎儿神经组织中平面细胞极性基因的体细胞突变。

寻求神经管缺陷（NTDs）致病突变的广泛研究迄今产生的有限阳性结果。造成这种情况的一个可能原因是，许多研究仅限于种系突变的分析，因此在NTD病例中可能遗漏了其他非种系突变。我们假设平面极性途径（PCP）基因的体细胞突变可能在NTD的发展中发挥作用。Torrent™个人基因组机™（PGM）测序用于从48例病变部位和脐带组织中提取的成对DNA样本中的选定PCP基因。Sanger测序用于验证检测到的突变。研究了来自不同细菌层的组织中经验证的突变的来源和分布。亚细胞定位，蛋白质印迹，进行了荧光素酶和荧光素酶测定以更好地了解突变对蛋白质定位，蛋白质水平和途径信号传导的影响。ix体细胞突变得到鉴定和验证，表明在不同组织中分布多样。三个体细胞突变是新的/罕见的：CELSR1 p.Gln2125His，FZD6 p.Gln88Glu和VANGL1 p.Arg374His。FZD6 p.Gln88Glu导致其蛋白质从细胞质到细胞核的错误定位，并破坏了CELSR1和FZD6的共定位。在荧光素酶测定中，该突变影响了非经典的WNT信号传导。VANGL1 p.Arg374His破坏了CELSR1和VANGL1的共定位，增加了VANGL1的蛋白质水平，并影响了细胞迁移。总共有7/48（14.5％）的NTD病例包含体细胞PCP突变。PCP基因中的体细胞突变（例如，