title: A novel mutation (T65P) in the PAS domain of the human potassium channel HERG results in the long QT syndrome by trafficking deficiency.
abstract: The congenital long QT syndrome is a cardiac disease characterized by an increased susceptibility to ventricular arrhythmias. The clinical hallmark is a prolongation of the QT interval, which reflects a delay in repolarization caused by mutations in cardiac ion channel genes. Mutations in the HERG (human ether-à-go-go-related gene KCNH2 can cause a reduction in I(Kr), one of the currents responsible for cardiac repolarization. We describe the identification and characterization of a novel missense mutation T65P in the PAS (Per-Arnt-Sim) domain of HERG, resulting in defective trafficking of the protein to the cell membrane. Defective folding of the mutant protein could be restored by decreased cell incubation temperature and pharmacologically by cisapride and E-4031. When trafficking was restored by growing cells at 27 degrees C, the kinetics of the mutated channel resembled that of wild-type channels although the rate of activation, deactivation, and recovery from inactivation were accelerated. No positive evidence for the formation of heterotetramers was obtained by co-expression of wild-type with mutant subunits at 37 degrees C. As a consequence the clinical symptoms may be explained rather by haploinsufficiency than by dominant negative effects. This study is the first to relate a PAS domain mutation in HERG to a trafficking deficiency at body temperature, apart from effects on channel deactivation.
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D015153:Blotting, Western; D027682:Cation Transport Proteins; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D010375:Pedigree; D015221:Potassium Channels / Q000737:chemistry / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
chemical_list: D027682:Cation Transport Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG