title: D85N, a KCNE1 polymorphism, is a disease-causing gene variant in long QT syndrome.
abstract: OBJECTIVE
  This study aims to address whether D85N, a KCNE1 polymorphism, is a gene variant that causes long QT syndrome (LQTS) phenotype.
  
  
  BACKGROUND
  KCNE1 encodes the beta-subunit of cardiac voltage-gated K(+) channels and causes LQTS, which is characterized by the prolongation of the QT interval and torsades de pointes, a lethal arrhythmia. D85N, a KCNE1 polymorphism, is known to be a functional variant associated with drug-induced LQTS.
  
  
  METHODS
  In order to elucidate the prevalence and clinical significance of this polymorphism, we performed genetic screening in 317 LQTS probands. For comparison, we examined its presence in 496 healthy control subjects. We also conducted biophysical assays for the D85N variant in mammalian cells.
  
  
  RESULTS
  The allele frequency for D85N carriers was 0.81% in healthy people. In contrast, among LQTS probands, there were 1 homozygous and 23 heterozygous carriers (allele frequency 3.9%). Seven of 23 heterozygous carriers had additional mutations in LQTS-related genes, and 3 female subjects had documented factors predisposing to the symptom. After excluding these probands, the D85N prevalence was significantly higher compared with control subjects (allele frequency 2.1%, p < 0.05). In a heterologous expression study with Chinese hamster ovarian cells, KCNE1-D85N was found to exert significant loss-of-function effects on both KCNQ1- and KCNH2-encoded channel currents.
  
  
  CONCLUSIONS
  The KCNE1-D85N polymorphism was significantly more frequent in our LQTS probands. The functional variant is a disease-causing gene variant of LQTS phenotype that functions by interacting with KCNH2 and KCNQ1. Since its allele frequency was approximately 1% among control individuals, KCNE1-D85N may be a clinically important genetic variant.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Nishio
authors.forename: Takeru
authors.initials: T
authors.lastname: Makiyama
authors.forename: Hideki
authors.initials: H
authors.lastname: Itoh
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sakaguchi
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.forename: Yin-Zhi
authors.initials: YZ
authors.lastname: Gong
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Tomoya
authors.initials: T
authors.lastname: Ozawa
authors.forename: Wei-Guang
authors.initials: WG
authors.lastname: Ding
authors.forename: Futoshi
authors.initials: F
authors.lastname: Toyoda
authors.forename: Mihoko
authors.initials: M
authors.lastname: Kawamura
authors.forename: Masaharu
authors.initials: M
authors.lastname: Akao
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kimura
authors.forename: Toru
authors.initials: T
authors.lastname: Kita
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002648:Child; D006224:Cricetinae; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*
chemical_list: C489622:KCNE1 protein, human; D024642:Potassium Channels, Voltage-Gated