Identification of a Kir3.4 Mutation in Congenital Long QT Syndrome
Research output: Contribution to journal › Journal article › peer-review
Congenital long QT syndrome (LQTS) is a hereditary disorder that leads to sudden cardiac death secondary to fatal cardiac arrhythmias. Although many genes for LQTS have been described, the etiology remains unknown in 30%-40% of cases. In the present study, a large Chinese family (four generations, 49 individuals) with autosomal-dominant LQTS was clinically evaluated. Genome-wide linkage analysis was performed by using polymorphic microsatellite markers to map the genetic locus, and positional candidate genes were screened by sequencing for mutations. The expression pattern and functional characteristics of the mutated protein were investigated by western blotting and patch-clamp electrophysiology. The genetic locus of the LQTS-associated gene was mapped to chromosome 11q23.3-24.3. A heterozygous mutation (Kir3.4-Gly387Arg) was identified in the G protein-coupled, inwardly rectifying potassium channel subunit Kir3.4, encoded by the KCNJ5 gene. The Kir3.4-Gly387Arg mutation was present in all nine affected family members and absent in 528 ethnically matched controls. Western blotting of human cardiac tissue demonstrated significant Kir3.4 expression levels in the cardiac ventricles. Heterologous expression studies with Kir3.4-Gly387Arg revealed a loss-of-function electrophysiological phenotype resulting from reduced plasma membrane expression. Our findings suggest a role for Kir3.4 in the etiology of LQTS.
|Journal||American Journal of Human Genetics|
|Number of pages||9|
|Publication status||Published - 2010|
- Adolescent, Adult, Aged, Aminophylline, Atropine, Chromosome Mapping, Drug Combinations, Female, G Protein-Coupled Inwardly-Rectifying Potassium Channels, Genetic Linkage, Humans, Infant, Newborn, Long QT Syndrome, Male, Middle Aged, Mutation, Myocardium, Nitroglycerin, Papaverine, Pedigree, Phenobarbital