Genetic interactions between planar cell polarity genes cause diverse neural tube defects in mice.
Genetic interactions between planar cell polarity genes cause diverse neural tube defects in mice.
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DOI：
10.1242/dmm.016758
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发表时间：
2014-10
影响因子：
4.3
通讯作者：
Copp AJ
中科院分区：
文献类型：
--
作者：
Murdoch JN;Damrau C;Paudyal A;Bogani D;Wells S;Greene ND;Stanier P;Copp AJ
神经管缺陷（NTD）是最常见和最严重的发育缺陷形式之一，其特征在于中枢神经系统形成的早期胚胎事件的破坏。长期以来，NTD一直被认为表现出强烈的遗传依赖性，但遗传决定因素的身份仍然在很大程度上未被发现。平面细胞极性（PCP）通路基因突变纯合子小鼠神经管闭合的启动被破坏，这在NTDs和PCP信号传导之间提供了强有力的联系。最近，错义基因变异已被确定在PCP基因与NTD的人，虽然表型的范围是大于在小鼠突变体。此外，在受影响的人中检测到的序列变异是杂合的，并且通常可以在未受影响的个体中检测到。研究表明，多个杂合基因突变之间的相互作用导致人类NTD。为了确定在双杂合子中产生的表型，我们用Vangl 2Lp、ScribCrc和CelsrlCrsh突变的所有三种成对组合繁殖小鼠，这是最深入研究的PCP突变体。大多数双突变胚胎具有开放的NTD，其表型范围包括无脑畸形和脊柱裂，因此反映了在人类中观察到的缺陷。引人注目的是，即使在统一的遗传背景下，在不同的双杂合子组合之间也观察到突变表型的外显率和严重程度的变异性。表型上，Celsr 1Crsh; Vangl 2Lp;ScribCrc三重杂合突变体并不比双杂合或单纯合突变体更严重。我们提出，双突变表型之间的一些变化可以归因于每个等位基因中蛋白质破坏的性质：而ScribCrc是一个无效突变体，不产生Scrib蛋白，Celsr 1Crsh和Vangl 2Lp纯合子都表达突变蛋白，与显性效应一致。这些遗传相互作用的可变结果与人类患者直接相关，并强调了在人类中进行全面遗传筛查的重要性。
Neural tube defects (NTDs) are among the commonest and most severe forms of developmental defect, characterized by disruption of the early embryonic events of central nervous system formation. NTDs have long been known to exhibit a strong genetic dependence, yet the identity of the genetic determinants remains largely undiscovered. Initiation of neural tube closure is disrupted in mice homozygous for mutations in planar cell polarity (PCP) pathway genes, providing a strong link between NTDs and PCP signaling. Recently, missense gene variants have been identified in PCP genes in humans with NTDs, although the range of phenotypes is greater than in the mouse mutants. In addition, the sequence variants detected in affected humans are heterozygous, and can often be detected in unaffected individuals. It has been suggested that interactions between multiple heterozygous gene mutations cause the NTDs in humans. To determine the phenotypes produced in double heterozygotes, we bred mice with all three pairwise combinations of Vangl2Lp, ScribCrc and Celsr1Crsh mutations, the most intensively studied PCP mutants. The majority of double-mutant embryos had open NTDs, with the range of phenotypes including anencephaly and spina bifida, therefore reflecting the defects observed in humans. Strikingly, even on a uniform genetic background, variability in the penetrance and severity of the mutant phenotypes was observed between the different double-heterozygote combinations. Phenotypically, Celsr1Crsh;Vangl2Lp;ScribCrc triply heterozygous mutants were no more severe than doubly heterozygous or singly homozygous mutants. We propose that some of the variation between double-mutant phenotypes could be attributed to the nature of the protein disruption in each allele: whereas ScribCrc is a null mutant and produces no Scrib protein, Celsr1Crsh and Vangl2Lp homozygotes both express mutant proteins, consistent with dominant effects. The variable outcomes of these genetic interactions are of direct relevance to human patients and emphasize the importance of performing comprehensive genetic screens in humans.
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DOI：
10.1007/s12031-012-9871-9
发表时间：
2013-03
期刊：
Journal of molecular neuroscience : MN
影响因子：
--
作者：
De Marco P;Merello E;Consales A;Piatelli G;Cama A;Kibar Z;Capra V
通讯作者：
Capra V
DOI：
10.1242/dev.091173
发表时间：
2013-07
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Escobedo N;Contreras O;Muñoz R;Farías M;Carrasco H;Hill C;Tran U;Pryor SE;Wessely O;Copp AJ;Larraín J
通讯作者：
Larraín J
影响因子：
21.3
作者：
Devenport, Danelle;Fuchs, Elaine
通讯作者：
Fuchs, Elaine
影响因子：
3.5
作者：
Kibar Z;Salem S;Bosoi CM;Pauwels E;De Marco P;Merello E;Bassuk AG;Capra V;Gros P
通讯作者：
Gros P
影响因子：
1.1
作者：
Bartsch, O.;Kirmes, I.;Horn, F.
通讯作者：
Horn, F.