The long QT syndrome: a novel missense mutation in the S6 region of the KVLQT1 gene |
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Authors: | M H van den Berg Arthur A M Wilde E O Robles de Medina Henk Meyer J L M C Geelen Roselie J E Jongbloed Hein J J Wellens Joep P M Geraedts |
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Institution: | (1) Division of Genetics, University Maastricht, Joseph Bechlaan 113, 6229 GR Maastricht, The Netherlands, NL;(2) Heart Lung Institute, University of Utrecht, Utrecht, The Netherlands, NL;(3) Department of Clinical and Experimental Cardiology, Academic Medical Center (AMC), Amsterdam, The Netherlands, NL;(4) Clinical Genetics Limburg, Maastricht, The Netherlands, NL;(5) Department of Cardiology, Academic Hospital Maastricht (AZM), Maastricht, The Netherlands, NL;(6) Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands, NL |
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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.
Received: 25 March 1997 / Accepted: 21 April 1997 |
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