Hypokalemia-induced long QT syndrome with an underlying novel missense mutation in S4-S5 linker of KCNQ1

Novel Mutation in Hypokalemia-Induced LQTS. Congenital long QT syndrome (LQ TS) is caused by mutations in at least five genes coding for cardiac potass ium or sodium channels that regulate the duration of ventricular action pot entials. Acquired LOTS often is associated with drugs or metabolic abnormal ities. A 47-year-old woman who presented with marked QT prolongation (QTc = 620 msec(1/2)) and repeated episodes of torsades de pointes associated wit h hypokalemia (2.6 mEq/L) was screened for mutations in LOTS genes using po lymerase chain reaction/single-strand conformation polymorphism (PCR/SSCP). We identified a novel missense mutation in the intracellular linker of S4- S5 domains of KCNQ1, resulting in an amino acid substitution of cysteine fo r arginine at position 259 (R259C). Whole cell, patch clamp experiments wer e conducted on COS7 cells transfected with wild-type and/or R259C KCNQ1 wit h or without KCNE1. Functional analyses of the mutant KCNQ1 subunit on COS7 cells revealed its functional channels in the homozygous state, producing a significantly smaller current than the KCNQ1 channels and a less severe d ominant-negative effect on I-Ks. The novel KCNQ1 mutation R259C is the mole cular basis for I-Ks dysfunction underlying an apparently sporadic case of hypokalemia-induced LOTS, consistent with a mild mutation likely to disclos e the clinical manifestation of LOTS in a context of severe hypokalemia. Ou r findings suggest that gene carriers with such mild mutations might not be so rare as commonly expected in patients with acquired LOTS, and stress th e importance of mutational analysis for detecting either "silent" forms of congenital LOTS or de novo mutations.