Molecular mechanisms of Ellis‑van Creveld gene variations in ventricular septal defect.
Molecular mechanisms of Ellis‑van Creveld gene variations in ventricular septal defect.
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Ellis-van Creveld 基因变异在室间隔缺损中的分子机制
DOI：
10.3892/mmr.2017.8088
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发表时间：
2018-01
影响因子：
3.4
通讯作者：
Hong K
中科院分区：
文献类型：
--
作者：
Liu F;Liu X;Xu Z;Yuan P;Zhou Q;Jin J;Yan X;Xu Z;Cao Q;Yu J;Cheng Y;Wan R;Hong K
Ellis-van Creveld（EVC）基因与各种先天性心脏病有关。然而，关于室间隔缺损（VSD）中EVC基因变异及其分子机制的研究很少。本研究检测了65例VSD患者和210例正常对照的11个单核苷酸多态性（SNPs）。1727 G>A位点与VSD的发生呈正相关（P<0.007）。还鉴定了一种已知的突变c.343C>G，其导致EVC蛋白质（p.L115V）的氨基酸115处的亮氨酸至缬氨酸取代。功能预测结果表明c.343C>G可能是一个致病突变。此外，在NIH 3 T3小鼠胚胎成纤维细胞中，EVC c.343C>G突变显著降低细胞增殖并增加细胞凋亡。进一步的研究表明，在NIH 3 T3细胞中，EVC c.343C>G突变的过表达降低了EVC与smoothened的结合，进而下调了Hh信号通路的活性以及SAG下游cyclin D1和B-cell lymphoma 2蛋白的表达。EVC基因c.1727G>A SNP增加了中国汉族人群VSD的易感性EVC c.343C>G突变诱导VSD发生的分子机制可能是通过下调Hh通路活性降低心肌细胞的抗凋亡和增殖能力。本研究结果可能为VSD的诊断和治疗提供新的靶点。
The Ellis-van Creveld (EVC) gene is associated with various congenital heart diseases. However, studies on EVC gene variations in ventricular septal defect (VSD) and the underlying molecular mechanisms are sparse. The present study detected 11 single-nucleotide polymorphisms (SNPs) in 65 patients with VSD and 210 control patients from the Chinese Han population. Of the identified SNPs only the c.1727G>A SNP site was positively associated with the development of VSD (P<0.007). A known mutation, c.343C>G, was also identified, which causes a leucine to valine substitution at amino acid 115 of the EVC protein (p.L115V). The results of functional prediction indicated that c.343C>G may be a pathogenic mutation. In addition, in NIH3T3 mouse embryonic fibroblast cells, the EVC c.343C>G mutation significantly decreased cell proliferation and increased apoptosis. Further investigation demonstrated that in NIH3T3 cells, overexpression of EVC c.343C>G mutation reduced the binding between EVC and smoothened, which further downregulated the activity of the hedgehog (Hh) signaling pathway and the expression of downstream cyclin D1 and B-cell lymphoma 2 proteins with SAG. The c.1727G>A SNP of the EVC gene increased VSD susceptibility in patients from the Chinese Han population. The molecular mechanism underlying the development of VSD induced by the EVC c.343C>G mutation may be due to a reduction in the anti-apoptotic and proliferative abilities of cardiomyocytes via downregulation of Hh pathway activity. The results of the present study may provide novel targets for the diagnosis and treatment of patients with VSD.
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影响因子：
3.7
作者：
Serra-Juhé C;Cuscó I;Homs A;Flores R;Torán N;Pérez-Jurado LA
通讯作者：
Pérez-Jurado LA
影响因子：
2.7
作者：
Karki R;Pandya D;Elston RC;Ferlini C
通讯作者：
Ferlini C
影响因子：
3.5
作者：
Must, Anne;Koks, Sulev;Vali, Marika
通讯作者：
Vali, Marika
影响因子：
4.7
作者：
Tang, Hongwei;Wei, Peng;Li, Donghui
通讯作者：
Li, Donghui
影响因子：
4.1
作者：
Pacheco, Maria;Valencia, Maria;Ruiz-Perez, Victor L.
通讯作者：
Ruiz-Perez, Victor L.