KCNQ1 Gain-of-Function Mutation in Familial Atrial Fibrillation

TLDR

Atrial fibrillation is a common arrhythmia with poorly understood molecular causes, and the KCNQ1 gene encodes the pore‑forming α subunit of several cardiac potassium channels. The study aimed to identify the genetic cause of hereditary persistent AF in a family, pinpointing the S140G mutation in KCNQ1. Genetic sequencing of affected family members identified the S140G mutation in KCNQ1. Functional studies revealed that the S140G mutation produces a gain‑of‑function in KCNQ1/KCNE1 and KCNQ1/KCNE2 currents, shortening atrial action potential duration and refractory period, thereby likely driving AF.

Abstract

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 α subunit of the cardiac I Ks 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.