A Novel Missense Mutation of GATA4 in a Chinese Family with Congenital Heart Disease.
A Novel Missense Mutation of GATA4 in a Chinese Family with Congenital Heart Disease.
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中国先天性心脏病家系中 GATA4 的新错义突变
DOI：
10.1371/journal.pone.0158904
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Sun K
中科院分区：
文献类型：
--
作者：
Zhang X;Wang J;Wang B;Chen S;Fu Q;Sun K
背景先天性心脏病（CHD）是人类最常见的出生缺陷类型，在婴儿中发病率很高。已鉴定出几种对心脏发育至关重要的基因。 GATA4是调节心脏发育的关键转录因子。在不同类型的先心病患者中已发现许多 GATA4 突变。目的 在这项研究中，对一个跨越三代的家族（其中 7 名患者患有 CHD）的 NKX2-5、HAND1 和 GATA4 编码区进行了测序。通过生物信息学程序评估该家族中潜在的致病变异，并通过双荧光素酶报告基因测定分析突变蛋白的转录活性。结果 鉴定出一种新的 GATA4 突变 c.C931T (p.R311W)，并与该家族中受影响的患者共分离。生物信息学程序预测这种杂合突变是有害的，GATA4 序列的跨物种比对表明该突变发生在高度保守的氨基酸内。尽管突变蛋白位于核定位信号域，但它并没有改变其细胞内分布。然而，进一步的荧光素酶报告基因检测表明，p.R311W 突变降低了 GATA4 激活其下游靶基因的能力。结论 我们的研究发现了 GATA4 中的一个新突变，该突变可能导致该家族的先心病。这一发现扩大了 GATA4 突变谱，并强调了 GATA4 突变与 CHD 之间的致病相关性。
Background Congenital heart disease (CHD) is the most prevalent type of birth defect in human, with high morbidity in infant. Several genes essential for heart development have been identified. GATA4 is a pivotal transcription factor that can regulate the cardiac development. Many GATA4 mutations have been identified in patients with different types of CHD. Aims In this study, the NKX2-5, HAND1 and GATA4 coding regions were sequenced in a family spanning three generations in which seven patients had CHD. Disease-causing potential variation in this family was evaluated by bioinformatics programs and the transcriptional activity of mutant protein was analyzed by the dual luciferase reporter assay. Results A novel GATA4 mutation, c.C931T (p.R311W), was identified and co-segregated with the affected patients in this family. The bioinformatics programs predicted this heterozygous mutation to be deleterious and the cross-species alignment of GATA4 sequences showed that the mutation occurred within a highly conserved amino acid. Even though it resided in the nuclear localization signal domain, the mutant protein didn’t alter its intracellular distribution. Nevertheless, further luciferase reporter assay demonstrated that the p.R311W mutation reduced the ability of GATA4 to activate its downstream target gene. Conclusions Our study identified a novel mutation in GATA4 that likely contributed to the CHD in this family. This finding expanded the spectrum of GATA4 mutations and underscored the pathogenic correlation between GATA4 mutations and CHD.