Shanghai Jiao Tong University School of Medicine, Shanghai Chest Hospital, Department of Nuclear Medicine, Shanghai 200030, China.
Clinics (Sao Paulo). 2013 Jun;68(6):777-84. doi: 10.6061/clinics/2013(06)09.
The aim of this study was to evaluate the prevalence and spectrum of Nkx2.5 mutations associated with idiopathic atrial fibrillation (AF).
A cohort of 136 unrelated patients with idiopathic atrial fibrillation and 200 unrelated, ethnically matched healthy controls were enrolled. The coding exons and splice junctions of the Nkx2.5 gene were sequenced in 136 atrial fibrillation patients, and the available relatives of mutation carriers and 200 controls were subsequently genotyped for the identified mutations. The functional characteristics of the mutated Nkx2.5 gene were analyzed using a dual-luciferase reporter assay system.
Two novel heterozygous Nkx2.5 mutations (p.N19D and p.F186S) were identified in 2 of the 136 unrelated atrial fibrillation cases, with a mutational prevalence of approximately 1.47%. These missense mutations co-segregated with atrial fibrillation in the families and were absent in the 400 control chromosomes. Notably, 2 mutation carriers also had congenital atrial septal defects and atrioventricular block. Multiple alignments of the Nkx2.5 protein sequences across various species revealed that the altered amino acids were completely conserved evolutionarily. Functional analysis demonstrated that the mutant Nkx2.5 proteins were associated with significantly reduced transcriptional activity compared to their wild-type counterpart.
These findings associate the Nkx2.5 loss-of-function mutation with atrial fibrillation and atrioventricular block and provide novel insights into the molecular mechanism involved in the pathogenesis of atrial fibrillation. These results also have potential implications for early prophylaxis and allele-specific therapy of this common arrhythmia.
本研究旨在评估与特发性心房颤动（AF）相关的 Nkx2.5 突变的流行率和谱。
纳入了 136 名特发性心房颤动患者和 200 名无关的、种族匹配的健康对照者组成队列。对 136 名心房颤动患者的 Nkx2.5 基因编码外显子和剪接接头进行测序，并对突变携带者的可用亲属和 200 名对照者进行随后的基因分型，以鉴定所识别的突变。使用双荧光素酶报告基因检测系统分析突变的 Nkx2.5 基因的功能特征。
在 136 名无关的心房颤动病例中发现了 2 种新的杂合 Nkx2.5 突变（p.N19D 和 p.F186S），其突变发生率约为 1.47%。这些错义突变在家族中与心房颤动共分离，在 400 个对照染色体中不存在。值得注意的是，2 名突变携带者还患有先天性房间隔缺损和房室传导阻滞。在不同物种的 Nkx2.5 蛋白序列的多重比对中发现，改变的氨基酸在进化上是完全保守的。功能分析表明，与野生型相比，突变的 Nkx2.5 蛋白与转录活性显著降低相关。
这些发现将 Nkx2.5 功能丧失性突变与心房颤动和房室传导阻滞相关联，并为心房颤动发病机制中涉及的分子机制提供了新的见解。这些结果还可能对这种常见心律失常的早期预防和等位基因特异性治疗具有重要意义。
