BackgroundAtrial fibrillation (AF) is the most common form of clinical cardiac dysrhythmia responsible for thromboembolic cerebral stroke, congestive heart failure, and death. Aggregating evidence highlights the strong genetic basis of AF. Nevertheless, AF is of pronounced genetic heterogeneity, and in an overwhelming majority of patients, the genetic determinants underpinning AF remain elusive.Methods and ResultsBy genome‐wide screening with polymorphic microsatellite markers and linkage analysis in a 4‐generation Chinese family affected with autosomal‐dominant AF, a novel locus for AF was mapped to chromosome 1q24.2–q25.1, a 3.20‐cM (≈4.19 Mbp) interval between markers D1S2851 and D1S218, with the greatest 2‐point logarithm of odds score of 4.8165 for the marker D1S452 at recombination fraction=0.00. Whole‐exome sequencing and bioinformatics analyses showed that within the mapping region, only the mutation in the paired related homeobox 1 (PRRX1) gene, NM_022716.4:c.319C>T;(p.Gln107*), cosegregated with AF in the family. In addition, sequencing analyses of PRRX1 in another cohort of 225 unrelated patients with AF revealed a new mutation, NM_022716.4:c.437G>T; (p.Arg146Ile), in a patient. The 2 mutations were absent in 908 control subjects. Biological analyses in HeLa cells demonstrated that the 2 mutants had significantly diminished transactivation on the target genes ISL1 and SHOX2 and markedly decreased ability to bind the promoters of ISL1 and SHOX2 (2 genes causally linked to AF), although with normal intracellular distribution.ConclusionsThis study first indicates that PRRX1 loss‐of‐function mutations predispose to AF, which provides novel insight into the molecular pathogenesis underpinning AF, implying potential implications for precisive prophylaxis and management of AF.

中文翻译：

---

家族性心房颤动的 PRRX1 功能丧失突变

背景心房颤动 (AF) 是临床心律失常的最常见形式，可导致血栓栓塞性脑卒中、充血性心力衰竭和死亡。综合证据强调了 AF 的强大遗传基础。然而，AF 具有明显的遗传异质性，在绝大多数患者中，支持 AF 的遗传决定因素仍然难以捉摸。显性 AF，AF 的一个新基因座被定位到染色体 1q24.2-q25.1，标记 D1S2851 和 D1S218 之间的间隔为 3.20-cM（≈4.19 Mbp），最大的 2 点对数比值得分为 4.8165重组分数 = 0.00 处的标记 D1S452。PRRX1 )基因，NM_022716.4:c.319C>T;(p.Gln107*)，在家族中与AF共同分离。此外，另一组 225 名无关 AF 患者的PRRX1测序分析揭示了一个新的突变，NM_022716.4:c.437G>T；(p.Arg146Ile)，在患者中。908 名对照受试者中没有这 2 种突变。HeLa 细胞的生物学分析表明，2 个突变体对靶基因ISL1和SHOX2的反式激活显着降低，与ISL1和SHOX2启动子的结合能力显着降低（2 个基因与 AF 有因果关系），尽管细胞内分布正常。结论本研究首先表明 PRRX1 功能丧失突变易患 AF，这为支持 AF 的分子发病机制提供了新的见解，这意味着对精确预防和管理的潜在影响的 AF。