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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Genetic interaction between members of the Vangl family causes neural tube defects in mice
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Genetic interaction between members of the Vangl family causes neural tube defects in mice

机译：Vangl家族成员之间的遗传相互作用导致小鼠神经管缺陷

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摘要

Neural tube defects (NTDs) are very frequent congenital abnormalities in humans. Recently, we have documented independent association of Vangl1 and Vangl2 gene mutations with NTDs. In the Looptail mouse, homozygosity (but not heterozygosity) for loss-of-function alleles at Vangl2 causes the severe NTD craniorachis-chisis, whereas heterozygosity for mutant variants of VANGL1 is associated with NTDs in a human cohort of sporadic and familial cases. To understand the role of Vangli in normal development, we created a mouse mutant with an inactivating mutation at Vangli (Vangl1~(gt)). Vangl1 shows a dynamic pattern of expression in the developing neural tube and notochord at the time of neural tube closure. Vangl1~(gt/+) heterozygotes and Vangl1~(gt/gt) homozygotes are viable and fertile, although Vangl1~(gt/gt) display subtle alterations in polarity of inner hair cells of the cochlea. Remarkably, and as opposed to healthy Vangl1~(gt/+) and Vangl2~(lp/+) heterozygotes, Vangl1~(gt/+); Vangl2~(lp/+) double heterozygotes show profound developmental defects that include severe craniorachischisis, inner ear defects (disorganization of the stereociliary bundles of hair cells of the organ of Corti), and cardiac abnormality (aberrant right sub-clavian artery). These results show that genetic interaction between Vangl1 and Vangl2 genes causes neural tube defects and raise the possibility that interaction between individual Vangl genes and other genetic loci and/or environmental factors may additionally contribute to the etiology of NTDs.
机译：神经管缺陷（NTD）是人类中非常常见的先天性异常。最近，我们已经记录了Vangl1和Vangl2基因突变与NTD的独立关联。在Looptail小鼠中，Vangl2的功能丧失等位基因的纯合性（而非杂合性）导致严重的NTD颅-chisis，而VANGL1突变体的杂合性与人零星和家族性病例中的NTD相关。为了了解Vangli在正常发育中的作用，我们创建了一个在Vangli处具有失活突变的小鼠突变体（Vangl1〜（gt））。 Vangl1在神经管闭合时在发育中的神经管和脊索中显示了动态表达模式。 Vangl1〜（gt / +）杂合子和Vangl1〜（gt / gt）纯合子是活的和可育的，尽管Vangl1〜（gt / gt）在耳蜗内毛细胞的极性上显示出细微的变化。值得注意的是，与健康的Vangl1〜（gt / +）和Vangl2〜（lp / +）杂合子相反，Vangl1〜（gt / +）; Vangl2〜（lp / +）双重杂合子显示出严重的发育缺陷，包括严重的颅achi裂，内耳缺陷（Corti器官的毛细血管束的立体睫状束紊乱）和心脏异常（右锁骨下动脉异常）。这些结果表明，Vangl1和Vangl2基因之间的遗传相互作用会引起神经管缺陷，并增加单个Vangl基因与其他遗传基因座和/或环境因素之间的相互作用可能进一步导致NTD病因的可能性。

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