Novel GATA4 mutations in lone atrial fibrillation
Novel GATA4 mutations in lone atrial fibrillation
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孤立性心房颤动中的新 GATA4 突变
DOI：
10.3892/ijmm.2011.783
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发表时间：
2011-12-01
影响因子：
5.4
通讯作者：
Yang, Yi-Qing
中科院分区：
文献类型：
--
作者：
Jiang, Jin-Qi;Shen, Fang-Fang;Yang, Yi-Qing
心房颤动（AF）是最常见的心律失常，是发病率和死亡率的主要原因。先前的研究已经确定遗传缺陷是少数患者房颤的危险因素。然而，房颤具有很大的遗传异质性，在大多数病例中，房颤的分子决定因素尚不清楚。在这项研究中，研究人员对160例无血缘关系的单纯性心房纤颤患者的GATA4的整个编码序列和剪接进行了测序。GATA4编码一种对心脏发生至关重要的锌指转录因子。对携带已确定突变的患者的现有亲属进行基因分型。利用荧光素酶报告基因检测系统分析了突变体GATA4的功能特征。结果，在2个不相关的AF家族中分别鉴定出p.G16C和p.H28D两个新的杂合GATA4突变，并在每个家族中与AF共分离，具有完全外显率。功能分析表明，GATA4突变与转录活性显著降低有关。这些发现扩大了与房颤相关的GATA4突变谱，并为房颤发病的分子机制提供了新的见解。
Atrial fibrillation (AF) is the most frequent cardiac arrhythmia and is a major cause of morbidity and mortality. Previous studies have established genetic defects as a risk factor for AF in a minority of patients. However, AF is of substantial genetic heterogeneity and the molecular determinants for AF in a majority of cases remain unclear. In this study, the entire coding sequence and splice junctions of GATA4, which encodes a zinc-finger transcription factor essential for cardiogenesis, were sequenced in 160 unrelated patients with lone AF. A total of 200 unrelated ethnically matched healthy individuals were used as controls. The available relatives of the patient carrying an identified mutation were genotyped. The functional characteristics of the mutant GATA4 were analyzed using a luciferase reporter assay system. As a result, two novel heterozygous GATA4 mutations of p.G16C and p.H28D, were identified in 2 unrelated families with AF, respectively, which co-segregated with AF in each family with complete penetrance. Functional analysis demonstrated that the mutations of GATA4 were associated with a significantly decreased transcriptional activity. The findings expand the mutation spectrum of GATA4 linked to AF and provide novel insight into the molecular mechanism involved in the pathogenesis of AF.