Homozygous Deletion in KVLQT1 Associated With Jervell and Lange-Nielsen Syndrome

Abstract

Background-Long-QT (LQT) syndrome is a cardiac disorder that causes syncope, seizures, and sudden death from ventricular arrhythmias, specifically torsade de pointes. Both autosomal dominant LQT (Romano-Ward syndrome) and autosomal recessive LQT (Jervell and Lange-Nielsen syndrome, JLNS) have been reported. Heterozygous mutations in 3 potassium channel genes, KVLQT1, KCNE1 (minK), and HERG, and the cardiac sodium channel gene SCN5A cause autosomal dominant LQT. Autosomal recessive LQT, which is associated with deafness, has been found to occur with homozygous mutations in KVLQT1 and KCNE1 in JLNS families in which QTc prolongation was inherited as a dominant trait. Methods and Results-An Amish family with clinical evidence of JLNS was analyzed for mutations by use of single-strand conformation polymorphism and DNA sequencing analyses for mutations in all known LQT genes. A novel homozygous 2-bp deletion in the S2 transmembrane segment of KVLQT1 was identified in affected members of this Amish family in which both QTc prolongation and deafness were inherited as recessive traits. This deletion represents a new JLNS-associated mutation in KVLQT1 and has deleterious effects on the KVLQT1 potassium channel, causing a frameshift and the truncation of the KVLQT1 protein. In contrast to previous reports in which LQT was inherited as a clear dominant trait, 2 parents in the JLNS family described here have normal QTc intervals (0.43 and 0.44 seconds, respectively). Conclusions-A novel homozygous KVLQT1 mutation causes JLNS in an Amish family with deafness that is inherited as an autosomal recessive trait. (Circulation. 1999;99:1344-1347.)

The "Final Common Pathway" Hypothesis and Inherited Cardiovascular Disease

“…Since mutations in KVLQT1 cause chromosome 11-linked LQTS, LQT1, mutations in minK were also expected to cause LQTS, and this fact was subsequently demonstrated [74]. Homozygous mutations or compound heterozygous mutations in KVLQT1 have been shown to cause Jervell and Lange-Nielsen syndrome [17,50,52], suggesting that the deafness seen in Jervell and Lange-Nielsen syndrome is autosomal recessive while LQTS is autosomal dominant. Filamente) beobachtet.…”

Cellular distribution of the potassium channel KCNQ1 in normal mouse kidney

“…In the inner ear, KCNQ1 mediates K ϩ secretion into the endolymph, which is important for normal inner ear function (5,31). Humans with certain KCNQ1 gene mutations exhibit the autosomal recessive Jervell and Lange-Nielsen syndrome, which is manifested as hearing loss in addition to cardiac conduction abnormalities (6,41). KCNQ1-homozygous mutant mice also exhibit cochlear deafness, as well as circling, head bobbing, and inability to right themselves during a fall, indicative of vestibular dysfunction (5,19).…”

Mutational Consequences of Aberrant Ion Channels in Neurological Disorders

“…It begins in childhood and patient suffers with deafness, recurrent fainting, ventricular arrhythmia and sometimes sudden death (Schwartz et al 2006). Genetic mutations were reported in KCNQ1 and KCNE1 genes that codes for voltage gated delayed rectifier potassium channel's a and b subunit respectively in J-LN patients which is responsible for potassium ion imbalance in the cochlear hair cells and cardiomyocytes (Chen et al 1999;Tyson et al 2000). For normal hearing, a continuous flow of endolymph is required into the cochlear hair cells that are known to maintain the voltage gradient for nerve signal transmission (Lasak et al 2014), thus mutated channel disrupts the voltage gradient required for transmitting signal through auditory nerves thereby causing deafness.…”