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.

Genetics of Long QT Syndrome

“…24 in vitro heterologous expression studies revealed a loss-of-function electrophysiological phenotype associated with reduced plasma membrane expression. all mutation-positive family members experienced recurrent palpitations, 10 of 12 with recurrent syncope, and 5 with either persistent or permanent atrial fibrillation (af) or atrial tachycardia (at).…”

Cardiac Channelopathies: Disease at the Tip of a Patch Electrode

“…Several studies suggest that the mutations cause "misofolding" of Kv11.1 and cellular quality control mechanisms prevent its export into the secretory pathway (Ficker 2003;Delisle et al, 2005, Gong et al, 2005Gong et al, 2006;Walker et al, 2007;Walker et al, 2010;Li et al, 2010). Indeed, many different molecular chaperone proteins that regulate the trafficking of WT-Kv11.1 and LQT2 mutations have been identified (Figure 7).…”

Genetics of primary hyperaldosteronism

“…The Kir3.4 channel is an inward rectifier channel that is very selective for monovalent ions and remarkably discriminate between K + and Na + ions (Roux 2005). Loss-of-function germline mutations in KCNJ5 have been reported in congenital long QT syndrome (Yang et al 2010). …”