A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome

Abstract

The Jervell and Lange-Nielsen (JLN) syndrome (MIM 220400) is an inherited autosomal recessive disease characterized by a congenital bilateral deafness associated with a QT prolongation on the electrocardiogram, syncopal attacks due to ventricular arrhythmias and a high risk of sudden death. JLN syndrome is a rare disease, which seems to affect less than one percent of all deaf children. Linkage to chromosome 11p15.5 markers was found by analysing four consanguinous families. Recombinants allowed us to map the JLN gene between D11S922 and D11S4146, to a 6-cM interval where KVLQT1, a potassium channel gene causing Romano-Ward (RW) syndrome, the dominant form of long QT syndrome, has been previously localized. An homozygous deletion-insertion event (1244, -7 +8) in the C-terminal domain of this gene was detected in three affected children of two families. We found that KVLQT1 is expressed in the stria vascularis of mouse inner ear by in situ hybridization. Taken together, our data indicate that KVLQT1 is responsible for both JLN and RW syndromes and has a key role not only in the ventricular repolarization but also in normal hearing, probably via the control of endolymph homeostasis.

Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss

“…Mutations in KCNQ1 cause the autosomal recessive Jervell and Lange‐Nielsen syndrome [MIM 220400], characterized by SNHL and cardiac abnormalities (long QT syndrome) (Jervell and Lange‐Nielsen, 1957; Neyroud et al, 1997). In this syndrome, there is an impaired K + secretion into the endolymph by the KCNQ1/KCNE1 channel complex on the apical membranes of the marginal cells in the stria vascularis, as confirmed in a mouse model with the homozygous mutants being completely deaf (Lee et al, 2000).…”

Variations in KCNQ1 are associated with type 2 diabetes and beta cell function in a Chinese population

“…Previous studies reported that KCNQ1 mutations were associated with long QT syndrome [8] and familial atrial fibrillation [9]. GWA scans have recently linked KCNQ1 to susceptibility to type 2 diabetes in a Japanese population [2,3].…”

Molecular Genetics of Vestibular Organ Development

“…Isk encodes a transmembrane protein that assembles with potassium channel subunits including Kcnq1. Mutations in both KCNQ1 and KCNE1 cause Jervell and Lange-Nielsen syndrome in humans (Neyroud et al 1997;Schulze-Bahr et al 1997), a syndrome associated with ventricular tachyarrhythmias of the heart and deafness. Knockout mouse models for both genes show a collapsed membranous labyrinth indicative of endolymph secretion failure and disruption of fluid homeostasis in the inner ear (Vetter et al 1996;Lee et al 2000;Casimiro et al 2001).…”

“…Kcnq1(Kvlqt1) or isk (KCNE1) are both expressed in the marginal cells of the stria (Sakagami et al 1991;Wangemann et al 1995;Neyroud et al 1997). Kcnq1 encodes a potassium channel subunit in the same family as Kcnq4.…”