Loss-of-function mutations of the K(+) channel gene KCNJ2 constitute a rare cause of long QT syndrome

Détails

ID Serval
serval:BIB_42A1687DA8C6
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Loss-of-function mutations of the K(+) channel gene KCNJ2 constitute a rare cause of long QT syndrome
Périodique
Journal of Molecular and Cellular Cardiology
Auteur(s)
Fodstad  H., Swan  H., Auberson  M., Gautschi  I., Loffing  J., Schild  L., Kontula  K.
ISSN
0022-2828 (Print)
Statut éditorial
Publié
Date de publication
08/2004
Volume
37
Numéro
2
Pages
593-602
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Aug
Résumé
Mutations of the KCNJ2 gene encoding the potassium channel Kir2.1 were previously shown to cause Andersen's syndrome (AS), a multisystem disease manifesting with developmental abnormalities, cardiac arrhythmias and periodic paralyses. We conducted a search for KCNJ2 mutations among 188 unrelated patients suspected to have long QT syndrome (LQTS). The screening was performed by denaturing high-performance liquid chromatography (dHPLC) and DNA sequencing. Two novel mutations of the KCNJ2 gene were detected: a missense threonine to alanine mutation (T75A) in the N-terminal region (family 1) and an in-frame deletion of two amino acids (DeltaFQ163-164) in the M2 transmembrane region (family 2). In addition, a previously described silent polymorphism C1146T was detected. In family 1, some of the affected family members had a history of periodic muscle weakness characteristic of AS, but no dysmorphic features. The mean QTc interval of the affected members were 444 +/- 24 ms (family 1, n=7) and 456 +/- 8 ms (family 2, n=2). The mutations affect functionally important regions of the KCNJ2 channel protein: upon injection of the Xenopus oocytes with the wild type and mutant KCNJ2 constructs, the channel proteins were correctly synthesized and localized to the cell surface, but no measurable inward K(+) current could be detected for the mutant KCNJ2 constructs. In conclusion, we report two novel loss-of-function mutations of the KCNJ2 channel, affecting different domains of the channel protein. Mutations of the KCNJ2 gene should be considered in genetic subclassification of LQTS patients, even in the absence of overt manifestations of AS.
Mots-clé
Amino Acid Sequence Animals Female Gene Expression Humans Long QT Syndrome/*genetics Male Molecular Sequence Data *Mutation, Missense Oocytes/metabolism Pedigree Potassium Channels, Inwardly Rectifying/analysis/*genetics/metabolism RNA, Complementary/genetics Sequence Alignment *Sequence Deletion Transfection Xenopus
Pubmed
Web of science
Création de la notice
24/01/2008 13:55
Dernière modification de la notice
20/08/2019 14:45
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