TBX5功能缺失性基因突变可致房颤和心手综合征
TBX5功能缺失性基因突变可致房颤和心手综合征
复制标题
DOI：
--
复制
发表时间：
2016
影响因子：
3.4
通讯作者：
XING‐BIAO QIU
中科院分区：
文献类型：
--
作者：
DONG‐FENG GUO;RUO‐GU LI;FANG YUAN;HONG‐YU SHI;XU‐MIN HOU;XIN‐KAI QU;YING‐JIA XU;MIN ZHANG;XU LIU;JIN‐QI JIANG;YI‐QING YANG;XING‐BIAO QIU
先前的全基因组关联研究已经证明，T-box（TBX）5中的单核苷酸多态性与房颤（AF）易感性增加相关，最近的一项研究将TBX 5突变与非典型Holt-Oram综合征和阵发性AF因果联系起来。然而，AF患者中TBX 5突变的患病率和谱仍有待阐明。在本研究中，前瞻性招募了190名无血缘关系的特发性房颤患者，招募了400名无血缘关系的健康个体作为对照。对参与者的TBX 5基因的编码外显子和侧翼内含子进行测序。使用双荧光素酶报告基因测定系统，与其野生型对应物相比，描述了突变体TBX 5的功能特征。结果，在1例AF患者中发现了一种新的杂合TBX 5突变p.P132S，突变发生率约为0.53%。先证者家族的遗传分析显示，该突变与AF共分离，并以常染色体显性模式传播。错义突变在800条对照染色体中不存在，并且改变的氨基酸在物种间完全进化保守。功能分析表明，突变体TBX 5的转录活性显着降低。此外，该突变显着降低了TBX 5和NK 2同源框5之间的协同激活，这是另一种与AF有因果关系的转录因子。据我们所知，本研究是第一个报告TBX 5功能缺失突变与AF易感性增加之间的关联。这些结果为AF的分子机制提供了新的见解，并且在AF（持续性心律失常的最常见形式）的新型预防和治疗策略的开发中具有潜在的意义。
Previous genome‐wide association studies have demonstrated that single nucleotide polymorphisms in T‐box (TBX)5 are associated with increased susceptibility to atrial fibrillation (AF), and a recent study has causally linked a TBX5 mutation to atypical Holt‐Oram syndrome and parox‐ ysmal AF. However, the prevalence and spectrum of TBX5 mutations in patients with AF remain to be elucidated. In the present study, a cohort of 190 unrelated patients with idio‐ pathic AF were prospectively recruited, with 400 unrelated healthy individuals recruited as controls. The coding exons and flanking introns of the TBX5 gene were sequenced in the participants. The functional characteristics of the mutant TBX5 were delineated in contrast with its wild‐type counter‐ part using a dual‐luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.P132S, was identified in an index patient with AF, with a mutational prevalence of ~0.53%. Genetic analysis of the proband's family showed that the mutation co‐segregated with AF, and was transmitted in an autosomal dominant pattern. The missense mutation was absent in the 800 control chromosomes, and the altered amino acid was completely evolutionarily conserved across species. Functional analyses revealed that the mutant TBX5 had significantly reduced transcriptional activity. Furthermore, the mutation markedly decreased the synergistic activation between TBX5 and NK2 homeobox 5, another transcription factor which has been causatively linked to AF. The present study was the first, to the best of our knowledge, to report on the association between a TBX5 loss‐of‐function mutation and increased susceptibility to AF. These results provide novel insight into the molecular mechanism underpinning AF, and have potential implications in the development of novel prophylactic and therapeutic strategies for AF, the most common form of sustained cardiac arrhythmia.