特发性房颤致病基因的识别

Atrial fibrillation (AF) is a common cardiac arrhythmia whose molecular etiology is poorly understood. We studied a family with hereditary persistent AF and identified the causative mutation (S140G) in the KCNQ1 (KvLQT1) gene on chromosome 11p15.5. The KCNQ1 gene encodes the pore-forming subunit of the cardiac IKs channel (KCNQ1/KCNE1), the KCNQ1/KCNE2 and the KCNQ1/KCNE3 potassium channels. Functional analysis of the S140G mutant revealed a gain-of-function effect on the KCNQ1/KCNE1 and the KCNQ1/KCNE2 currents, which contrasts with the dominant negative or loss-of-function effects of the KCNQ1 mutations previously identified in patients with long QT syndrome. Thus, the S140G mutation is likely to initiate and maintain AF by reducing action potential duration and effective refractory period in atrial myocytes.

在已经获得2个特发性房颤（IAf）家系基础之上，首先通过候选基因策略直接筛查心脏钠通道、钾通道和缝隙连接通道等基因，如果它们不是IAf致病基因，那么则采用高效能解卷滤ㄎ⑽佬腔蚍中头椒ê蚅ods连锁分析技术确定IAf基因座，最后运用基因组信息学，通过定位候选策略，利用PCR-SSCP和DNA测序技术，首次识别IAf致病基因。