Functional analysis of rare variants of GATA4 identified in Chinese patients with congenital heart defect
Functional analysis of rare variants of GATA4 identified in Chinese patients with congenital heart defect
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中国先天性心脏病患者中发现的 GATA4 罕见变异的功能分析
DOI：
10.1002/dvg.23333
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发表时间：
2019
期刊：
影响因子：
1.5
通讯作者：
Guoying Huang
中科院分区：
文献类型：
--
作者：
Zhengshan Zhao;Yongkun Zhan;Weicheng Chen;Xiaojing Ma;Wei Sheng;Guoying Huang
先天性心脏病 (CHD) 是最常见的心血管疾病之一，影响约 0.8% 的活产儿。众所周知，转录因子 GATA4 在心脏发育中发挥着关键作用。在本研究中，我们对 9 名不相关的 CHD 患者进行了全外显子组测序，并在 3 例病例中发现了 GATA4 基因中两种罕见的有害错义变异（c.C487T、p.P163S 和 c.C1223A、p.P408Q）（ExAC <0.001 和 CADD >15），并经 Sanger 测序证实。随后，通过桑格测序在另外 226 名 CHD 患者和 206 名健康对照中筛查了这两种变异，没有观察到变异。使用功能预测程序预测这两种变体会损害蛋白质功能。 Co-IP 表明，两种 GATA4 变体（P163S 和 P408Q）均阻断 GATA4 和 ZFPM2 蛋白之间异二聚体的形成。免疫荧光显示，与 WT 蛋白相比，两种 GATA4 变体减少了 GATA4 和 ZFPM2 蛋白之间的共定位形成。这些发现表明GATA4的两种罕见变异可能干扰其与ZFPM2的相互作用并影响相应的下游基因活性，提示GATA4变异可能与CHD的发病机制有关。
Congenital heart defect (CHD) is one of the most common cardiovascular diseases, affecting approximately 0.8% of live births. The transcription factor GATA4 has been known to play a key role in cardiac development. In this study, we performed whole exome sequencing in nine unrelated CHD patients and found two rare deleterious missense variants in theGATA4gene (c.C487T,p.P163S and c.C1223A,p.P408Q) (ExAC <0.001 and CADD >15) in three cases that were confirmed by Sanger sequencing. Subsequently, these two variants were screened for in an additional 226 patients with CHD and 206 healthy controls by Sanger sequencing, and no variants were observed. These two variants were predicted to be damaging to protein function using a functional prediction program. Co‐IP indicated that both of the GATA4 variants (P163S and P408Q) blocked heterodimer formation between GATA4 and ZFPM2 protein. Immunofluorescence showed that the two GATA4 variants diminished the colocalization formation between GATA4 and ZFPM2 protein compared to that of WT protein. These findings indicate that the two rare variants of GATA4 might disturb its interaction with ZFPM2 and influence corresponding downstream gene activity, suggesting that theGATA4variants may be associated with the pathogenesis of CHD.