Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations
Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations
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DOI：
10.1093/hmg/ddn411
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发表时间：
2009-03-01
影响因子：
3.5
通讯作者：
Ware, Stephanie M.
中科院分区：
文献类型：
--
作者：
Mohapatra, Bhagyalaxmi;Casey, Brett;Ware, Stephanie M.
已知NODAL及其信号通路在脊椎动物胚胎的特化和图案化中起关键作用。编码NODAL信号通路组分的几个基因中的突变先前已被认为与人类左右（LR）图案缺陷的发病机制有关。因此，NODAL，TGF-β超家族的发育调节因子的成员，是一个强有力的候选人，在功能上参与先天性LR轴图案缺陷或异位。在这里，我们已经调查了是否在NODAL的变异存在于异位和/或孤立的心血管畸形（CVM）的患者被认为是由异常的心管环。一个大型队列的情况下（n = 269）受影响的经典异位或循环CVM的分析显示，四个不同的错义变异，一个框内插入/缺失和两个保守的剪接位点变异在14个无关的主题（14/269，5.2%）。尽管与其他相关缺陷相似，但与未检测到NODAL突变的病例相比，NODAL突变个体的肺动脉瓣闭锁发生率显著较高（P = 0.001）。功能分析表明，NODAL的错义变体形式表现出显著的信号传导损伤，如通过减少Cripto（TDGF-1）共受体介导的人工报告基因的激活所测量的。这些NODAL蛋白的表达也导致Smad 2磷酸化诱导减少和Smad 2核输入受损。总之，这些结果支持NODAL中的突变和罕见有害变体作为散发性人类LR图案化缺陷的原因的作用。
NODAL and its signaling pathway are known to play a key role in specification and patterning of vertebrate embryos. Mutations in several genes encoding components of the NODAL signaling pathway have previously been implicated in the pathogenesis of human left-right (LR) patterning defects. Therefore, NODAL, a member of TGF-beta superfamily of developmental regulators, is a strong candidate to be functionally involved in congenital LR axis patterning defects or heterotaxy. Here we have investigated whether variants in NODAL are present in patients with heterotaxy and/or isolated cardiovascular malformations (CVM) thought to be caused by abnormal heart tube looping. Analysis of a large cohort of cases (n = 269) affected with either classic heterotaxy or looping CVM revealed four different missense variants, one in-frame insertion/deletion and two conserved splice site variants in 14 unrelated subjects (14/269, 5.2%). Although similar with regard to other associated defects, individuals with the NODAL mutations had a significantly higher occurrence of pulmonary valve atresia (P = 0.001) compared with cases without a detectable NODAL mutation. Functional analyses demonstrate that the missense variant forms of NODAL exhibit significant impairment of signaling as measured by decreased Cripto (TDGF-1) co-receptor-mediated activation of artificial reporters. Expression of these NODAL proteins also led to reduced induction of Smad2 phosphorylation and impaired Smad2 nuclear import. Taken together, these results support a role for mutations and rare deleterious variants in NODAL as a cause for sporadic human LR patterning defects.