R231C mutation in KCNQ1 causes long QT syndrome type 1 and familial atrial fibrillation

Daniel C. Bartos, Sabine Duchatelet, Don E. Burgess, Didier Klug, Isabelle Denjoy, Rachel Peat, Jean Marc Lupoglazoff, Vronique Fressart, Myriam Berthet, Michael J. Ackerman, Craig T. January, Pascale Guicheney, Brian P. Delisle

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Background Loss-of-function mutations in the gene KCNQ1 encoding the Kv7.1 K+ channel cause long QT syndrome type 1 (LQT1), whereas gain-of-function mutations are associated with short QT syndrome as well as familial atrial fibrillation (FAF). However, KCNQ1 mutation pleiotropy, which is capable of expressing both LQT1 and FAF, has not been demonstrated for a discrete KCNQ1 mutation. The genotypephenotype relationship for a family with FAF suggests a possible association with the LQT1 p.Arg231Cys-KCNQ1 (R231C-Q1) mutation. Objective The purpose of this study was to determine whether R231C-Q1 also can be linked to FAF. Methods The R231C-Q1 proband with AF underwent genetic testing for possible mutations in 10 other AF-linked genes plus KCNH2 and SCN5A. Sixteen members from five other R231C-positive LQT1 families were genetically tested for 21 single nucleotide polymorphisms (SNPs) to determine if the FAF family had discriminatory SNPs associated with AF. R231C-Q1 was expressed with KCNE1 (E1) in HEK293 cells, and Q1E1 currents (IQ1E1) were analyzed using the whole-cell patch-clamp technique. Results Genetic analyses revealed no additional mutations or discriminatory SNPs. Cells expressing WT-Q1 and R231C-Q1 exhibited some constitutively active I Q1E1 and smaller maximal IQ1E1 compared to cells expressing WT-Q1. Conclusion Constitutively active IQ1E1 and a smaller peak IQ1E1 are common features of FAF-associated and LQT1-associated mutations, respectively. These data suggest that the mixed functional properties of R231C-Q1 may predispose some families to LQT1 or FAF. We conclude that R231C is a pleiotropic missense mutation capable of LQT1 expression, AF expression, or both.

Original languageEnglish (US)
Pages (from-to)48-55
Number of pages8
JournalHeart rhythm
Volume8
Issue number1
DOIs
StatePublished - Jan 2011

Keywords

  • Atrial fibrillation
  • Familial atrial fibrillation
  • Genetics
  • Ion channel
  • KCNQ1
  • Long QT syndrome
  • Long QT syndrome type 1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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