title: The long QT syndrome: a novel missense mutation in the S6 region of the KVLQT1 gene.
abstract: The Romano Ward long QT syndrome (LQTS) has an autosomal dominant mode of inheritance. Patients suffer from syncopal attacks often resulting in sudden cardiac death. The main diagnostic parameter is a prolonged QT(c) interval as judged by electro-cardiographic investigation. LQTS is a genetically heterogeneous disease with four loci having been identified to date: chromosome 11p15.5 (LQT1), 7q35-36 (LQT2), 3p21-24 (LQT3) and 4q25-26 (LQT4). The corresponding genes code for potassium channels KVLQT1 (LQT1) and HERG (LQT2) and the sodium channel SCN5A (LQT3). The KVLQT1 gene is characterized by six transmembrane domains (S1-S6), a pore region situated between the S5 and S6 domains and a C-terminal domain accounting for approximately 60% of the channel. This domain is thought to be co-associated with another protein, viz. minK (minimal potassium channel). We have studied a Romano Ward family with several affected individuals showing a severe LQTS phenotype (syncopes and occurrence of sudden death). Most affected individuals had considerable prolongations of QT(c). By using haplotyping with a set of markers covering the four LQT loci, strong linkage was established to the LQT1 locus, whereas the other loci (LQT2, LQT3 and LQT4) could be excluded. Single-strand conformation polymorphism analysis and direct sequencing were used to screen the KVLQT1 gene for mutations in the S1-S6 region, including the pore domain. We identified a Gly-216-Arg substitution in the S6 transmembrane domain of KVLQT1. The mutation was present in all affected family members but absent in normal control individuals, providing evidence that the mutated KVLQT1-gene product indeed caused LQTS in this family. The mutated KVLQT1-gene product thus probably results in a dominant negative suppression of channel activity.
authors.affiliation: Division of Genetics, University Maastricht, The Netherlands.
authors.forename: M H
authors.initials: MH
authors.lastname: van den Berg
authors.forename: A A
authors.initials: AA
authors.lastname: Wilde
authors.forename: E O
authors.initials: EO
authors.lastname: Robles de Medina
authors.forename: H
authors.initials: H
authors.lastname: Meyer
authors.forename: J L
authors.initials: JL
authors.lastname: Geelen
authors.forename: R J
authors.initials: RJ
authors.lastname: Jongbloed
authors.forename: H J
authors.initials: HJ
authors.lastname: Wellens
authors.forename: J P
authors.initials: JP
authors.lastname: Geraedts
mesh_terms: D004252:DNA Mutational Analysis; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated
chemical_list: D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated