title: Transgenic mice overexpressing human KvLQT1 dominant-negative isoform. Part I: Phenotypic characterisation.
abstract: OBJECTIVE
  The KCNQ1 gene encodes the KvLQT1 potassium channel, which generates in the human heart the slow component of the cardiac delayed rectifier current, I(Ks). Mutations in KCNQ1 are the most frequent cause of the congenital long QT syndrome. We have previously cloned a cardiac KCNQ1 human isoform, which exerts a strong dominant-negative effect on KvLQT1 channels. We took advantage of this dominant-negative isoform to engineer an in vivo model of KvLQT1 disruption, obtained by overexpressing the dominant-negative subunit under the control of the alpha-myosin heavy chain promoter.
  
  
  RESULTS
  Three different transgenic lines demonstrated a phenotype with increasing severity. Functional suppression of KvLQT1 in transgenic mice led to a markedly prolonged QT interval associated with sinus node dysfunction. Transgenic mice also demonstrated atrio-ventricular block leading to occasional Wenckebach phenomenon. The atrio-ventricular block was associated with prolonged AH but normal HV interval in His recordings. Prolonged QT interval correlated with prolonged action potential duration and with reduced K(+) current density in patch-clamp experiments. RNase protection assay revealed remodeling of K(+) channel expression in transgenic mice.
  
  
  CONCLUSIONS
  Our transgenic mouse model suggests a role for KvLQT1 channels not only in the mouse cardiac repolarisation but also in the sinus node automaticity and in the propagation of the impulse through the AV node.
authors.affiliation: INSERM U533, Laboratoire de Physiopathologie et de Pharmacologie Cellulaires et Moléculaires G & R Laennec, Faculté de Médecine, 1 rue Gaston Veil, 44035 Nantes cedex 01, France.
authors.forename: S
authors.initials: S
authors.lastname: Demolombe
authors.forename: G
authors.initials: G
authors.lastname: Lande
authors.forename: F
authors.initials: F
authors.lastname: Charpentier
authors.forename: M A
authors.initials: MA
authors.lastname: van Roon
authors.forename: M J
authors.initials: MJ
authors.lastname: van den Hoff
authors.forename: G
authors.initials: G
authors.lastname: Toumaniantz
authors.forename: I
authors.initials: I
authors.lastname: Baro
authors.forename: G
authors.initials: G
authors.lastname: Guihard
authors.forename: N
authors.initials: N
authors.lastname: Le Berre
authors.forename: A
authors.initials: A
authors.lastname: Corbier
authors.forename: J
authors.initials: J
authors.lastname: de Bakker
authors.forename: T
authors.initials: T
authors.lastname: Opthof
authors.forename: A
authors.initials: A
authors.lastname: Wilde
authors.forename: A F
authors.initials: AF
authors.lastname: Moorman
authors.forename: D
authors.initials: D
authors.lastname: Escande
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D004562:Electrocardiography; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D018408:Patch-Clamp Techniques; D010641:Phenotype; D015221:Potassium Channels / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated
chemical_list: D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; C496910:Kcnq1 protein, mouse; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated