In vivo identification of genes that modify ether-a-go-go-related gene activity in Caenorhabditis elegans may also affect human cardiac arrhythmia.
Human ether-a-go-go-related gene (HERG) encodes the pore-forming subunit of I(Kr), a cardiac K(+) channel. Although many commonly used drugs block I(Kr), in certain individuals, this action evokes a paradoxical life-threatening cardiac rhythm disturbance, known as the acquired long QT syndrome (aLQTS). Although aLQTS has become the leading cause of drug withdrawal by the U.S. Food and Drug Administration, DNA sequencing in aLQTS patients has revealed HERG mutations only in rare cases, suggesting that unknown HERG modulators are often responsible. By using the worm Caenorhabditis elegans, we have developed in vivo behavioral assays that identify candidate modulators of unc-103, the worm HERG orthologue. By using RNA-interference methods, we have shown that worm homologues of two HERG-interacting proteins, Hyperkinetic and K channel regulator 1 (KCR1), modify unc-103 function. Examination of the human KCR1 sequence in patients with drug-induced cardiac repolarization defects revealed a sequence variation (the substitution of isoleucine 447 by valine, I447V) that occurs at a reduced frequency (1.1%) relative to a matched control population (7.0%), suggesting that I447V may be an allele for reduced aLQTS susceptibility. This clinical result is supported by in vitro studies of HERG dofetilide sensitivity by using coexpression of HERG with wild-type and I447V KCR1 cDNAs. Our studies demonstrate the feasibility of using C. elegans to assay and potentially identify aLQTS candidate genes.
Department of Anesthesiology and Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
Christina I
CI
Petersen
Toni R
TR
McFarland
Svetlana Z
SZ
Stepanovic
Ping
P
Yang
David J
DJ
Reiner
Kenshi
K
Hayashi
Alfred L
AL
George
Dan M
DM
Roden
James H
JH
Thomas
Jeffrey R
JR
Balser
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D004594:Electrophysiology; D006801:Humans; D008124:Locomotion / Q000235:genetics; D009038:Motion; D009154:Mutation; D009468:Neuromuscular Diseases / Q000235:genetics; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid
D029742:Caenorhabditis elegans Proteins; D015221:Potassium Channels; C474006:UNC-103 protein, C elegans; C490706:algn-10 protein, C elegans