Coding and non-coding variants in the SHOX2 gene in patients with early-onset atrial fibrillation.
Coding and non-coding variants in the SHOX2 gene in patients with early-onset atrial fibrillation.
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DOI：
10.1007/s00395-016-0557-2
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发表时间：
2016-05
影响因子：
9.5
通讯作者：
Rappold GA
中科院分区：
文献类型：
--
作者：
Hoffmann S;Clauss S;Berger IM;Weiß B;Montalbano A;Röth R;Bucher M;Klier I;Wakili R;Seitz H;Schulze-Bahr E;Katus HA;Flachsbart F;Nebel A;Guenther SP;Bagaev E;Rottbauer W;Kääb S;Just S;Rappold GA
心房颤动（AF）是最常见的心律失常，具有很强的遗传成分。涉及同源域转录因子Shox 2的分子途径控制小鼠和斑马鱼心脏传导系统的发育和功能。在这里，我们报告分析人类SHOX 2作为早发性AF的潜在易感基因。为了识别因果变异并定义潜在机制，分析了378例60岁以前早发性AF患者的结果，并与1870例对照或参考数据集进行比较。我们发现了两个错义突变（p.G81E，p.H283Q），被预测为破坏性的。在斑马鱼中使用SHOX 2靶标和表型拯救实验的反式激活研究表明，p.H283Q突变严重影响SHOX 2起搏器功能。我们还证明了3′UTR变异c.* 28 T> SHOX 2和AF的C（p = 0.00515）。携带这种变体的患者PR间隔明显更长。从机制上讲，该变体产生了hsa-miR-92 b-5 p的功能性结合位点。在携带3′UTR变异体的AF患者中，循环hsa-miR-92 b-5 p血浆水平显著改变（p = 0.0095）。最后，我们证明房颤患者右心耳SHOX 2表达水平显著低于窦性心律患者。总之，这些结果表明SHOX 2在早发性AF中的遗传贡献。本文的在线版本（doi：10.1007/s 00395 -016-0557-2）包含补充材料，可供授权用户使用。
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia with a strong genetic component. Molecular pathways involving the homeodomain transcription factor Shox2 control the development and function of the cardiac conduction system in mouse and zebrafish. Here we report the analysis of human SHOX2 as a potential susceptibility gene for early-onset AF. To identify causal variants and define the underlying mechanisms, results from 378 patients with early-onset AF before the age of 60 years were analyzed and compared to 1870 controls or reference datasets. We identified two missense mutations (p.G81E, p.H283Q), that were predicted as damaging. Transactivation studies using SHOX2 targets and phenotypic rescue experiments in zebrafish demonstrated that the p.H283Q mutation severely affects SHOX2 pacemaker function. We also demonstrate an association between a 3′UTR variant c.*28T>C of SHOX2 and AF (p = 0.00515). Patients carrying this variant present significantly longer PR intervals. Mechanistically, this variant creates a functional binding site for hsa-miR-92b-5p. Circulating hsa-miR-92b-5p plasma levels were significantly altered in AF patients carrying the 3′UTR variant (p = 0.0095). Finally, we demonstrate significantly reduced SHOX2 expression levels in right atrial appendages of AF patients compared to patients with sinus rhythm. Together, these results suggest a genetic contribution of SHOX2 in early-onset AF. The online version of this article (doi:10.1007/s00395-016-0557-2) contains supplementary material, which is available to authorized users.