Molecular characterization of two founder mutations causing long QT syndrome and identification of compound heterozygous patients.

Details

Serval ID
serval:BIB_30AD4032C81A
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Molecular characterization of two founder mutations causing long QT syndrome and identification of compound heterozygous patients.
Journal
Annals of Medicine
Author(s)
Fodstad H., Bendahhou S., Rougier J.S., Laitinen-Forsblom P.J., Barhanin J., Abriel H., Schild L., Kontula K., Swan H.
ISSN
0785-3890
Publication state
Published
Issued date
2006
Peer-reviewed
Oui
Volume
38
Number
4
Pages
294-304
Language
english
Abstract
BACKGROUND: Mutations of at least six different genes have been found to cause long QT syndrome (LQTS), an inherited arrhythmic disorder characterized by a prolonged QT interval on the electrocardiogram (ECG), ventricular arrhythmias and risk of sudden death. AIM: The aims were to define the yet undetermined phenotypic characteristics of two founder mutations and to study clinical features in compound heterozygotes identified during the course of the study. METHODS: To maximize identification of the compound heterozygotes, we used an extended group of LQTS patients comprising 700 documented or suspected cases. Functional studies were carried out upon transient expression in COS-7 or HEK293 cells. RESULTS: The KCNQ1 IVS7-2A>G (KCNQ1-FinB) mutation associated with a mean QTc interval of 464 ms and a complete loss-of-channel function. The HERG R176W (HERG-FinB) mutation caused a reduction in current density as well as slight acceleration of the deactivation kinetics in vitro, and its carriers had a mean QTc of 448 ms. The HERG R176W mutation was also present in 3 (0.9%) out of 317 blood donors. A total of six compound heterozygotes were identified who had the HERG R176W mutation in combination with a previously reported LQTS mutation (KCNQ1 G589D or IVS7-2A>G). When present simultaneously with an apparent LQTS-causing mutation, the HERG R176W mutation may exert an additional in vivo phenotypic effect. CONCLUSIONS: The HERG R176W mutation represents a population-prevalent mutation predisposing to LQTS. Compound heterozygosity for mutant LQTS genes may modify the clinical picture in LQTS.
Keywords
Adult, Animals, COS Cells, Cercopithecus aethiops, Child, Preschool, Ether-A-Go-Go Potassium Channels, Female, Finland, Heterozygote, Heterozygote Detection, Humans, KCNQ1 Potassium Channel, Long QT Syndrome, Male, Membrane Potentials, Muscle Proteins, Mutation, Sodium Channels, Transfection
Pubmed
Web of science
Create date
24/01/2008 10:56
Last modification date
20/08/2019 13:15
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