title: Identification of a Kir3.4 mutation in congenital long QT syndrome.
abstract: 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.
authors.affiliation: Key Laboratory of Arrhythmias, Ministry of Education, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Yanzong
authors.initials: Y
authors.lastname: Yang
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Yang
authors.forename: Bo
authors.initials: B
authors.lastname: Liang
authors.forename: Jinqiu
authors.initials: J
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
authors.forename: Søren-Peter
authors.initials: SP
authors.lastname: Olesen
authors.forename: Hanne B
authors.initials: HB
authors.lastname: Rasmussen
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Ellinor
authors.forename: Lianjun
authors.initials: L
authors.lastname: Gao
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Lin
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Junjie
authors.initials: J
authors.lastname: Xiao
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Shulong
authors.initials: S
authors.lastname: Zhang
authors.forename: Dandan
authors.initials: D
authors.lastname: Liang
authors.forename: Luying
authors.initials: L
authors.lastname: Peng
authors.forename: Thomas
authors.initials: T
authors.lastname: Jespersen
authors.forename: Yi-Han
authors.initials: YH
authors.lastname: Chen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000628:Aminophylline; D001285:Atropine; D002874:Chromosome Mapping; D004338:Drug Combinations; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics* / Q000378:metabolism; D008040:Genetic Linkage; D006801:Humans; D007231:Infant, Newborn; D008133:Long QT Syndrome / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D005996:Nitroglycerin; D010208:Papaverine; D010375:Pedigree; D010634:Phenobarbital
chemical_list: D004338:Drug Combinations; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; C026863:Myocardon; D000628:Aminophylline; D001285:Atropine; D010208:Papaverine; D005996:Nitroglycerin; D010634:Phenobarbital