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Rare deleterious PARD3 variants in the aPKC-binding region are implicated in the pathogenesis of human cranial neural tube defects via disrupting apical tight junction formation

机译：aPKC结合区中的罕见有害PARD3变异体通过破坏根尖紧密连接形成而参与人类颅神经管缺陷的发病机制

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Increasing evidence that mutation of planar cell polarity (PCP) genes contributes to human cranial NTD susceptibility prompted us to hypothesize that rare variants of genes in the core apical–basal polarity (ABP) pathway are risk factors for cranial NTDs. In this study, we screened for rare genomic variation of PARD3 in 138 cranial NTD cases and 274 controls. Overall, the rare deleterious variants of PARD3 were significantly associated with increased risk for cranial NTDs (11/138 vs.7/274, p<0.05, OR=3.3). These NTD-specific variants were significantly enriched in the aPKC-binding region (6/138 vs. 0/274, p<0.01). The East Asian cohort in the ExAC database and another Chinese normal cohort further supported this association. Over-expression analysis in HEK293T and MDCK cells confirmed abnormal aPKC binding or interaction for two PARD3 variants (p.P913Q and p.D783G), resulting in defective tight junction formation via disrupted aPKC binding. Functional analysis in human neural progenitor cells and chick embryos revealed that PARD3 knockdown gave rise to abnormal cell polarity and compromised the polarization process of neuroepithelial tissue. Our studies suggest that rare deleterious variants of PARD3 in the aPKC-binding region contribute to human cranial NTDs, possibly by disrupting apical tight junction formation and subsequent polarization process of the neuroepithelium.
机译：越来越多的证据表明，平面细胞极性（PCP）基因的突变会导致人类颅脑NTD易感性，促使我们推测核心顶基极（ABP）通路中罕见的基因变异是颅脑NTD的危险因素。在这项研究中，我们筛选了138例颅脑NTD病例和274例对照的PARD3的罕见基因组变异。总体而言，PARD3的罕见有害变体与颅内NTD风险增加显着相关（11/138与7/274，p <0.05，OR = 3.3）。这些NTD特异性变体在aPKC结合区域显着富集（6/138对0/274，p <0.01）。 ExAC数据库中的东亚队列和另一个中国普通队列进一步支持了该协会。 HEK293T和MDCK细胞中的过表达分析证实了两种PARD3变体（p.P913Q和p.D783G）的aPKC结合异常或相互作用，导致通过破坏aPKC结合而形成紧密的紧密连接。对人类神经祖细胞和鸡胚的功能分析表明，PARD3敲低会引起异常的细胞极性，并损害神经上皮组织的极化过程。我们的研究表明，aPKC结合区中罕见的PARD3有害变异体可能通过破坏根尖紧密连接形成和随后的神经上皮极化过程而导致人颅NTD。

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