title: Clinical and electrophysiological characterization of a novel mutation R863X in HERG C-terminus associated with long QT syndrome.
abstract: We have found a novel nonsense mutation in the C-terminus of HERG in a four-generation Chinese family with long QT syndrome and investigated the molecular mechanism of this mutation in vitro. Six family members, including the proband, were clinically affected. Syncope and ventricular tachycardia of torsades de pointes were triggered by startling or emotional stress, and beta-adrenergic blockade treatment was ineffective. Haplotype analysis showed that only LQT2 markers cosegregated with the disease, and sequence analysis revealed a substitution of T with C at nucleotide position 2770 of the HERG gene (U04270), which creates a stop codon at amino acid position 863 (R863X) of the HERG protein, leading to a deletion of 296 amino acids. Whole cell patch clamp studies showed that the R863X HERG could not induce time-dependent current. Coexpression of R863X with wild-type HERG showed reduced current densities and accelerated voltage-dependent inactivation of HERG channels. Subcellular localization of R863X-EGFP revealed that the mutant did not traffic to the cell surface. These data suggest that R863X failed to form functional HERG channels, contributing to a prolongation of the QT interval and long QT syndrome with a dominant phenotype. These findings provide new insights into the structure-function relationships of the HERG C-terminus.
authors.affiliation: Sino-German Laboratory for Molecular Medicine and Center for Molecular Cardiology, Fuwai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 167 Beilishilu, 100037 Beijing, China.
authors.forename: Siyong
authors.initials: S
authors.lastname: Teng
authors.forename: Lijuan
authors.initials: L
authors.lastname: Ma
authors.forename: Yingxue
authors.initials: Y
authors.lastname: Dong
authors.forename: Chunxia
authors.initials: C
authors.lastname: Lin
authors.forename: Jue
authors.initials: J
authors.lastname: Ye
authors.forename: Robert
authors.initials: R
authors.lastname: Bähring
authors.forename: Vitya
authors.initials: V
authors.lastname: Vardanyan
authors.forename: Yanzong
authors.initials: Y
authors.lastname: Yang
authors.forename: Zhihu
authors.initials: Z
authors.lastname: Lin
authors.forename: Olaf
authors.initials: O
authors.lastname: Pongs
authors.forename: Rutai
authors.initials: R
authors.lastname: Hui
mesh_terms: D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D027682:Cation Transport Proteins / Q000737:chemistry / Q000235:genetics*; D002462:Cell Membrane / Q000378:metabolism; D003001:Cloning, Molecular; D006224:Cricetinae; D004252:DNA Mutational Analysis; D004594:Electrophysiology / Q000379:methods*; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D017353:Gene Deletion; D006239:Haplotypes; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D018613:Microscopy, Confocal; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010641:Phenotype; D015221:Potassium Channels / Q000737:chemistry / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated