title: Functional assessment of compound mutations in the KCNQ1 and KCNH2 genes associated with long QT syndrome.
abstract: BACKGROUND
  Long QT syndrome (LQTS) is a cardiovascular disorder characterized by prolonged QTc time, syncope, or sudden death caused by torsades de pointes and ventricular fibrillation. We investigated the clinical and electrophysiologic phenotype of individual mutations and the compound mutations in a family in which different genotypes could be found.
  
  
  OBJECTIVE
  The purpose of this study was to determine the impact of genotype-based diagnostic assessment in LQTS.
  
  
  METHODS
  We used cascade screening and functional analyses to investigate the phenotype in a family with LQTS. The contributions of the compound mutations in the KCNQ1 and KCNH2 genes (KCNQ1 R591H, KCNH2 R328C) were analyzed by heterologous expression in Xenopus laevis oocytes using two-electrode voltage clamp and by confocal imaging.
  
  
  RESULTS
  KCNH2 R328C did not show any functional phenotype whereas KCNQ1 R591H resulted in severe reduction of current. Neither wild-type nor mutant channels affected each other functionally in coexpression experiments. Therefore, a direct interaction between KCNQ1 and KCNH2 was ruled out under these conditions.
  
  
  CONCLUSIONS
  Assessment of novel mutational findings in LQTS should include accurate genetic and functional analysis. Notably, appropriate studies are needed if two or more mutations in different genes are present in one proband. Our findings prompt reconsideration of the impact of compound mutations in LQTS families and reinforce the need for thorough functional evaluation of novel ion channel mutations before assignment of pathogenic status.
authors.affiliation: Department of Medical Physiology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark. mgrunnet@mfi.ku.dk
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
authors.forename: Elijah Raphael
authors.initials: ER
authors.lastname: Behr
authors.forename: Kirstine
authors.initials: K
authors.lastname: Calloe
authors.forename: Jacob
authors.initials: J
authors.lastname: Hofman-Bang
authors.forename: Jan
authors.initials: J
authors.lastname: Till
authors.forename: Michael
authors.initials: M
authors.lastname: Christiansen
authors.forename: William John
authors.initials: WJ
authors.lastname: McKenna
authors.forename: Søren-Peter
authors.initials: SP
authors.lastname: Olesen
authors.forename: Nicole
authors.initials: N
authors.lastname: Schmitt
mesh_terms: D000483:Alleles; D004247:DNA / Q000235:genetics*; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006339:Heart Rate / Q000502:physiology; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics* / Q000378:metabolism; D008133:Long QT Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; D004247:DNA