GATA4 loss-of-function mutation underlies familial dilated cardiomyopathy
GATA4 loss-of-function mutation underlies familial dilated cardiomyopathy
复制标题
GATA4 功能丧失突变是家族性扩张型心肌病的基础
DOI：
10.1016/j.bbrc.2013.09.023
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发表时间：
2013-10-04
影响因子：
3.1
通讯作者：
Yang, Yi-Qing
中科院分区：
文献类型：
--
作者：
Li, Ruo-Gu;Li, Li;Yang, Yi-Qing
心脏转录因子GATA4对心脏发育至关重要，在动物模型和人类中，该基因的突变与多种先天性心脏病有关。然而，突变的GATA4是否易患扩张性心肌病（DCM）仍不清楚。本研究对110例无亲缘关系的特发性DCM患者的GATA4基因的整个编码区和剪接位点进行了测序。对携带确定突变的索引患者的现有亲属和200名不相关的种族匹配的健康个体作为对照进行基因分型。利用荧光素酶报告基因检测系统对突变体GATA4的功能效应进行了表征，并与野生型GATA4进行了对比。结果，在一个常染色体显性遗传DCM的家族中发现了一个新的杂合GATA4突变p.C271S，该突变与DCM在完全外显率的家族中共分离。400条对照染色体不存在错义突变，改变的氨基酸在种间进化上完全保守。功能分析表明，GATA4突变体与显著降低的转录活性和显著降低的GATA4与NKX2-5（另一个对心脏发生至关重要的转录因子）之间的协同激活有关。这些发现为DCM发病机制的分子机制提供了新的见解，提示了这种常见心肌疾病的产前诊断和基因特异性治疗的潜在意义。(C) 2013年作者。Elsevier Inc.出版。版权所有。
The cardiac transcription factor GATA4 is essential for cardiac development, and mutations in this gene have been implicated in a wide variety of congenital heart diseases in both animal models and humans. However, whether mutated GATA4 predisposes to dilated cardiomyopathy (DCM) remains unknown. In this study, the whole coding region and splice junction sites of the GATA4 gene was sequenced in 110 unrelated patients with idiopathic DCM. The available relatives of the index patient harboring an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were geno-typed. The functional effect of the mutant GATA4 was characterized in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous GATA4 mutation, p.C271S, was identified in a family with DCM inherited as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 400 control chromosomes and the altered amino acid was completely conserved evolutionarily among species. Functional analysis demonstrated that the GATA4 mutant was associated with significantly decreased transcriptional activity and remarkably reduced synergistic activation between GATA4 and NKX2-5, another transcription factor crucial for cardiogenesis. The findings provide novel insight into the molecular mechanisms involved in the pathogenesis of DCM, suggesting the potential implications in the prenatal diagnosis and gene-specific treatment for this common form of myocardial disorder. (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved.