Abstract 2326: The R231C KCNQ1 Mutation Causes Familial Atrial Fibrillation and Long QT Syndrome
KCNQ1 encodes a voltage-gated K+ channel α-subunit that underlies the slowly activating delayed rectifier K+ current (IKs) in the heart, and KCNQ1 mutations cause long and short QT syndromes (LQT1, SQTS2) and familial atrial fibrillation (FAF2). KCNQ1 mutations causing LQT typically result in a loss-of-function, whereas KCNQ1 mutations associated with FAF2 or SQT2 induce a gain-of-function. We identified a heterozygous R231C-KCNQ1 missense mutation in six families: one with FAF2 (four subjects, AF onset between 15 and 33 years) and the other five with LQT1 of which three probands were infants with fetal or neonatal LQT1 and bradycardia. Most carriers in LQT1 families are asymptomatic. To better understand the functional phenotype of R231C, we expressed the auxiliary K+ channel subunit KCNE1 and WT-KCNQ1, R231C-KCNQ1, or WT- and R231C-KCNQ1 cDNA (to mimic the dominant inheritance pattern) in HEK293 cells. We measured KCNQ1 current (IKCNQ1) by pulsing cells from −80 to 70 mV in 10-mV increments followed by a pulse to −50 mV. Cells expressing WT-KCNQ1/KCNE1 generated IKCNQ1 similar to IKs (n=34 cells); cells expressing R231C-KCNQ1/KCNE1 generated a gain-of-function phenotype and exhibited very large IKCNQ1 that was constitutively active at all membrane potentials tested (n=13 cells); and cells expressing WT-KCNQ1/R231C-KCNQ1/KCNE1 resulted in a mixed IKCNQ1 phenotype with voltage-dependent and constitutively active components (n=22 cells). Compared to cells expressing WT-KCNQ1/KCNE1, cells expressing WT-KCNQ1/R231C-KCNQ1/KCNE1 had larger IKCNQ1 at membrane potentials ≤0 mV (p<0.05) but smaller IKCNQ1 at membrane potentials ≥40 mV (p<0.05). The IKCNQ1 at negative membrane potentials resembled a gain-of-function phenotype similar to the FAF2 mutations S140G and V141M, however, the reduction in IKCNQ1 at positive membrane potentials mimicked the loss-of-function phenotype associated with LQT1 mutations. These unique functional characteristics may explain the mild and variable QT prolongation detected in most of the R231C carriers and the occurrence of FAF2 or LQT1 in different families. Although additional unknown factors may contribute to the phenotype variability, this study demonstrates that a single mutation is linked to FAF2 and LQT1.
This research has received full or partial funding support from the American Heart Association, National Center.