Polymorphism Screening in the Cardiac K+ Channel Gene KCNA5*

BACKGROUND: Common deoxyribonucleic acid polymorphisms that modulate normal cardiac electrophysiologic characteristics have previously been identified in long QT syndrome disease genes. In this study we screened an additional gene encoding the cardiac potassium channel KCNA5 (underlying I(Kur)) in 3 ethnic groups and evaluated the functional consequences of the variants identified. METHODS: The coding region was screened by single-stranded conformational polymorphism analysis and direct sequencing, and nonsynonymous variants were studied by patch-clamping transfected Chinese hamster ovary cells. Results Five synonymous and 6 nonsynonymous polymorphisms were found in KCNA5. None of these polymorphisms was present in greater than 7% of alleles screened or in all 3 ethnic groups. Expression of the nonsynonymous KCNA5 variants revealed normal gating. However, 2 variants (P532L and R578K, both in the C-terminus) were resistant to block by the prototypical inhibitor quinidine; the concentration required to block I(Kur) by 50% (IC(50)) was 8.4 micromol/L for wild type versus 54 micromol/L for R578K and 133 micromol/L for P532L (both P < .0001, versus wild type). CONCLUSION: KCNA5 displays little variability in its coding region. C-terminal KCNA5 variants displayed near-normal gating but striking resistance to drug block; thus these pharmacogenomic studies have identified a heretofore-unappreciated role of this region as a modulator of channel sensitivity to drugs. Resistance to I(Kur) blockers may be genetically determined.