b8e83b12-1e5a-4309-9728-a4e75a03bea6
title
Molecular and functional characterization of common polymorphisms in  HERG (KCNH2) ) potassium channels.
d91b6872-f987-4c97-8e64-d03c48f66a11
abstract
Long QT syndrome (LQTS) is a cardiac repolarization disorder that can lead to arrhythmias and sudden death. Chromosome 7-linked inherited LQTS (LQT2) is caused by mutations in human ether-a-go-go-related gene ( HERG ;  KCNH2 ), whereas drug-induced LQTS is caused primarily by  HERG  channel block. Many common polymorphisms are functionally silent and have been traditionally regarded as benign and without physiological consequence. However, the identification of common nonsynonymous single nucleotide polymorphisms (nSNPs; i.e., amino-acid coding variants) with functional phenotypes in the SCN5A Na(+) channel and MiRP1 K(+) channel beta-subunit have challenged this viewpoint. In this report, we test the hypothesis that common missense  HERG  polymorphisms alter channel physiology. Comprehensive mutational analysis of  HERG  was performed on genomic DNA derived from a population-based cohort of sudden infant death syndrome and two reference allele cohorts derived from 100 African American and 100 Caucasian individuals. Amino acid-encoding variants were considered common polymorphisms if they were present in at least two of the three study cohorts with an allelic frequency >0.5%. Four nSNPs were identified:  K897T ,  P967L ,  R1047L , and  Q1068R . Wild-type (WT) and polymorphic channels were heterologously expressed in human embryonic kidney cells, and biochemical and voltage-clamp techniques were used to characterize their functional properties. All channel types were processed similarly, but several electrophysiological differences were identified: 1)  K897T  current density was lower than the other polymorphic channels; 2)  K897T  channels activated at more negative potentials than WT and  R1047L ; 3)  K897T  and  Q1068R  channels inactivated and recovered from inactivation faster than WT,  P967L , and  R1047L  channels; and 4)  K897T  channels showed subtle differences compared with WT channels when stimulated with an action potential waveform. In contrast to  K897T  and  Q1068R  channels,  P967L  and  R1047L  channels were electrophysiologically indistinguishable from WT channels. All  HERG  channels had similar sensitivity to block by cisapride. Therefore, some  HERG  polymorphic channels are electrophysiologically different from WT channels.