title: Dominant-negative I(Ks) suppression by KCNQ1-deltaF339 potassium channels linked to Romano-Ward syndrome.
abstract: OBJECTIVE
  Hereditary long QT syndrome (LQTS) is a genetically heterogeneous disease characterized by prolonged QT intervals and an increased risk for ventricular arrhythmias and sudden cardiac death. Mutations in the voltage-gated potassium channel subunit KCNQ1 induce the most common form of LQTS. KCNQ1 is associated with two different entities of LQTS, the autosomal-dominant Romano-Ward syndrome (RWS), and the autosomal-recessive Jervell and Lange-Nielsen syndrome (JLNS) characterized by bilateral deafness in addition to cardiac arrhythmias. In this study, we investigate and discuss dominant-negative I(Ks) current reduction by a KCNQ1 deletion mutation identified in a RWS family.
  
  
  METHODS
  Single-strand conformation polymorphism analysis and direct sequencing were used to screen LQTS genes for mutations. Mutant KCNQ1 channels were heterologously expressed in Xenopus oocytes, and potassium currents were recorded using the two-microelectrode voltage clamp technique.
  
  
  RESULTS
  A heterozygous deletion of three nucleotides (CTT) identified in the KCNQ1 gene caused the loss of a single phenylalanine residue at position 339 (KCNQ1-deltaF339). Electrophysiological measurements in the presence and absence of the regulatory beta-subunit KCNE1 revealed that mutant and wild type forms of an N-terminal truncated KCNQ1 subunit (isoform 2) caused much stronger dominant-negative current reduction than the mutant form of the full-length KCNQ1 subunit (isoform 1).
  
  
  CONCLUSIONS
  This study highlights the functional relevance of the truncated KCNQ1 splice variant (isoform 2) in establishment and mode of inheritance in long QT syndrome. In the RWS family presented here, the autosomal-dominant trait is caused by multiple dominant-negative effects provoked by heteromultimeric channels formed by wild type and mutant KCNQ1-isoforms in combination with KCNE1.
authors.affiliation: Universitätsklinik Heidelberg, Innere Medizin III, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
authors.forename: Anna-Britt
authors.initials: AB
authors.lastname: Wimmer
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Karle
authors.forename: Manuela
authors.initials: M
authors.lastname: Licka
authors.forename: Markus
authors.initials: M
authors.lastname: Alter
authors.forename: Markus
authors.initials: M
authors.lastname: Khalil
authors.forename: Herbert E
authors.initials: HE
authors.lastname: Ulmer
authors.forename: Sven
authors.initials: S
authors.lastname: Kathöfer
authors.forename: Johann
authors.initials: J
authors.lastname: Kiehn
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schoels
authors.forename: Michael
authors.initials: M
authors.lastname: Koenen
authors.forename: Joerg
authors.initials: J
authors.lastname: Zehelein
mesh_terms: D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D005260:Female; D017353:Gene Deletion; D005799:Genes, Dominant; D006579:Heterozygote; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics*; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D009865:Oocytes; D018408:Patch-Clamp Techniques; D018807:Polymorphism, Single-Stranded Conformational; D029597:Romano-Ward Syndrome / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014981:Xenopus
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human