title: Identification and characterisation of a novel KCNQ1 mutation in a family with Romano-Ward syndrome.
abstract: Romano-Ward syndrome (RWS), the autosomal dominant form of the congenital long QT syndrome, is characterised by prolongation of the cardiac repolarisation process associated with ventricular tachyarrhythmias of the torsades de pointes type. Genetic studies have identified mutations in six ion channel genes, KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 and the accessory protein Ankyrin-B gene, to be responsible for this disorder. Single-strand conformation polymorphism (SSCP) analysis and subsequent DNA sequence analysis have identified a KCNQ1 mutation in a family that were clinically conspicuous due to several syncopes and prolonged QTc intervals in the ECG. The mutant subunit was expressed and functionally characterised in the Xenopus oocyte expression system. A novel heterozygous missense mutation with a C to T transition at the first position of codon 343 (CCA) of the KCNQ1 gene was identified in three concerned family members (QTc intervals: 500, 510 and 530 ms, respectively). As a result, proline 343 localised within the highly conserved transmembrane segment S6 of the KCNQ1 channel is replaced by a serine. Co-expression of mutant (KCNQ1-P343S) and wild-type (KCNQ1) cRNA in Xenopus oocytes produced potassium currents reduced by approximately 92%, while IKs reconstitution experiments with a combination of KCNQ1 mutant, wild-type and KCNE1 subunits yielded currents reduced by approximately 60%. A novel mutation (P343S) identified in the KCNQ1 subunit gene of three members of a RWS family showed a dominant-negative effect on native IKs currents leading to prolongation of the heart repolarisation and possibly increases the risk of malign arrhythmias with sudden cardiac death.
authors.affiliation: Innere Medizin III, Universitätsklinik Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. joerg_zehelein@med.uni-heidelberg.de
authors.forename: J
authors.initials: J
authors.lastname: Zehelein
authors.forename: D
authors.initials: D
authors.lastname: Thomas
authors.forename: M
authors.initials: M
authors.lastname: Khalil
authors.forename: A-B
authors.initials: AB
authors.lastname: Wimmer
authors.forename: M
authors.initials: M
authors.lastname: Koenen
authors.forename: M
authors.initials: M
authors.lastname: Licka
authors.forename: K
authors.initials: K
authors.lastname: Wu
authors.forename: J
authors.initials: J
authors.lastname: Kiehn
authors.forename: K
authors.initials: K
authors.lastname: Brockmeier
authors.forename: V A W
authors.initials: VA
authors.lastname: Kreye
authors.forename: C A
authors.initials: CA
authors.lastname: Karle
authors.forename: H A
authors.initials: HA
authors.lastname: Katus
authors.forename: H E
authors.initials: HE
authors.lastname: Ulmer
authors.forename: W
authors.initials: W
authors.lastname: Schoels
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D004594:Electrophysiology; D005260:Female; D015870:Gene Expression; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D011188:Potassium / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011392:Proline / Q000235:genetics; D029597:Romano-Ward Syndrome / Q000235:genetics*; D016415:Sequence Alignment; D014982:Xenopus laevis
chemical_list: D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D024642:Potassium Channels, Voltage-Gated; D011392:Proline; D011188:Potassium