title: A novel missense mutation causing a G487R substitution in the S2-S3 loop of human ether-à-go-go-related gene channel.
abstract: BACKGROUND
  Mutations of human ether-à-go-go-related gene (hERG), which encodes a cardiac K(+) channel responsible for the acceleration of the repolarizing phase of an action potential and the prevention of premature action potential regeneration, often cause severe arrhythmic disorders. We found a novel missense mutation of hERG that results in a G487R substitution in the S2-S3 loop of the channel subunit [hERG(G487R)] from a family and determined whether this mutant gene could induce an abnormality in channel function.
  
  
  RESULTS
  We made whole-cell voltage-clamp recordings from HEK-293T cells transfected with wild-type hERG [hERG(WT)], hERG(G487R), or both. We measured hERG channel-mediated current as the "tail" of a depolarization-elicited current. The current density of the tail current and its voltage- and time-dependences were not different among all the cell groups. The time-courses of deactivation, inactivation, and recovery from inactivation and their voltage-dependences were not different among all the cell groups. Furthermore, we performed immunocytochemical analysis using an anti-hERG subunit antibody. The ratio of the immunoreactivity of the plasma membrane to that of the cytoplasm was not different between cells transfected with hERG(WT), hERG(G487R), or both.
  
  
  CONCLUSIONS
  hERG(G487R) can produce functional channels with normal gating kinetics and cell-surface expression efficiency with or without the aid of hERG(WT). Therefore, neither the heterozygous nor homozygous inheritance of hERG(G487R) is thought to cause severe cardiac disorders. hERG(G487R) would be a candidate for a rare variant or polymorphism of hERG with an amino acid substitution in the unusual region of the channel subunit.
authors: Department of Legal Medicine Second, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors: Koshi
authors: K
authors: Kinoshita
authors: Yoshiaki
authors: Y
authors: Yamaguchi
authors: Kohki
authors: K
authors: Nishide
authors: Katsuya
authors: K
authors: Kimoto
authors: Yuki
authors: Y
authors: Nonobe
authors: Akira
authors: A
authors: Fujita
authors: Kenta
authors: K
authors: Asano
authors: Toshihide
authors: T
authors: Tabata
authors: Hisashi
authors: H
authors: Mori
authors: Hiroshi
authors: H
authors: Inoue
authors: Yukiko
authors: Y
authors: Hata
authors: Kenkichi
authors: K
authors: Fukurotani
authors: Naoki
authors: N
authors: Nishida
mesh_terms: D000200:Action Potentials; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D002462:Cell Membrane / Q000378:metabolism; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D015640:Ion Channel Gating; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D018408:Patch-Clamp Techniques; D010641:Phenotype; D011188:Potassium / Q000378:metabolism; D021122:Protein Subunits; D014162:Transfection; D055815:Young Adult
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D021122:Protein Subunits; D011188:Potassium