Dominant-Negative KvLQT1 Mutations Underlie the LQT1 Form of Long QT Syndrome

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Abstract
Background Mutations that map to the KvLQT1 gene on human chromosome 11 account for more than 50% of inherited long QT syndrome (LQTS). It has been discovered recently that the KvLQT1 and minK proteins functionally interact to generate a current with biophysical properties similar to I Ks , the slowly activating delayed-rectifier cardiac potassium current. Since I Ks modulates the repolarization of cardiac action potentials it is reasonable to hypothesize that mutations in KvLQT1 reduce I Ks , resulting in the prolongation of cardiac action potential duration. Methods and Results We expressed LQTS-associated Kv LQT1 mutants in Xenopus oocytes either individually or in combination with wild-type KvLQT1 or in combination with both wild-type KvLQT1 and minK. Substitutions of alanine with proline in the S2-S3 cytoplasmic loop (A177P) or threonine with isoleucine in the highly conserved signature sequence of the pore (T311I) yield inactive channels when expressed individually, whereas substitution of leucine with phenylalanine in the S5 transmembrane domain (L272F) yields a functional channel with reduced macroscopic conductance. However, all these mutants inhibit wild-type KvLQT1 currents in a dominant-negative fashion. Conclusions In LQTS-affected individuals these mutations would be predicted to result in a diminution of the cardiac I Ks current, subsequent prolongation of cardiac repolarization, and an increased risk of arrhythmias.