Human ether-a-go-go related gene (HERG) encodes the pore-forming subunit of IKr, a cardiac K+ channel. Many commonly-used drugs block IKr, which may lead to a life-threatening cardiac rhythm disturbance, known as the acquired long QT syndrome (aLQTS). However, DNA sequencing in aLQTS patients has revealed HERG mutations in only rare cases, suggesting unknown HERG-modulators are often responsible. We have developed in vivo behavioral assays in C. elegans, to identify candidate modulators of
unc-103, the worm HERG orthologue. Using a neomorphic mutant strain,
unc-103(
n500), with defects in locomotion, egg-laying and pharyngeal pumping, we employed RNA-interference methods (RNAi), to demonstrate that the worm homologue of KCR1, a protein which modifies K+ channel current in vitro, modifies
unc-103 activity in vivo. Examination of the human KCR1 sequence in patients with drug-induced cardiac repolarization defects revealed a sequence variation (I447V) that occurs at a reduced frequency (1.1%) relative to a matched control population (7.0%), suggesting I447V may be an allele for reduced aLQTS susceptibility. This clinical result is supported by in vitro studies of HERG dofetilide sensitivity, using coexpression of HERG with wild-type- and I447V-KCR1 cDNAs. These results led us to undertake an RNAi screen in C. elegans to identify novel modulators of
unc-103(
n500) activity in vivo. Two of the genes we identified in our RNAi screen,
eat-16, the worm RGS7 orthologue and C01F4.2a, the worm ARHGAP6 orthologue, modify the
unc-103(
n500) mutant phenotype when their gene activity is reduced. Additionally, the human orthologue of worm ARHGAP6 also modifies HERG current when coexpressed with the channel in CHO cells. These genes represent candidate HERG modifiers that will be tested for involvement in human cardiac rhythm disturbances.