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Identification and characterisation of a novel KCNQ1 mutation in a family with Romano-Ward syndrome.
- Source :
-
Biochimica et biophysica acta [Biochim Biophys Acta] 2004 Nov 05; Vol. 1690 (3), pp. 185-92. - Publication Year :
- 2004
-
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.
- Subjects :
- Amino Acid Sequence
Animals
Base Sequence
Cloning, Molecular
DNA Mutational Analysis
Electrophysiology
Female
Gene Expression
Humans
KCNQ Potassium Channels
KCNQ1 Potassium Channel
Male
Molecular Sequence Data
Oocytes metabolism
Patch-Clamp Techniques
Pedigree
Phenotype
Polymorphism, Single-Stranded Conformational
Potassium metabolism
Potassium Channels, Voltage-Gated chemistry
Proline genetics
Sequence Alignment
Xenopus laevis
Mutation genetics
Potassium Channels, Voltage-Gated genetics
Potassium Channels, Voltage-Gated metabolism
Romano-Ward Syndrome genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0006-3002
- Volume :
- 1690
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta
- Publication Type :
- Academic Journal
- Accession number :
- 15511625
- Full Text :
- https://doi.org/10.1016/j.bbadis.2004.06.024