Human Molecular Genetics, Vol 6, 2179-2185, Copyright © 1997 by Oxford University Press
J Tyson, L Tranebjaerg, S Bellman, C Wren, JF Taylor, J Bathen, B Aslaksen, SJ Sorland, O Lund, S Malcolm, M Pembrey, S Bhattacharya and M Bitner-Glindzicz
The Jervell and Lange-Nielsen syndrome (JLNS) comprises profound congenital
sensorineural deafness associated with syncopal episodes. These are caused
by ventricular arrhythmias secondary to abnormal repolarisation, manifested
by a prolonged QT interval on the electrocardiogram. Recently, in families
with JLNS, Neyroud et al. reported homozygosity for a single mutation in
KVLQT1 , a gene which has previously been shown to be mutated in families
with dominantly inherited isolated long QT syndrome [Neyroud et al . (1997)
Nature Genet ., 15, 186-189]. We have analysed a group of families with
JLNS and shown that the majority are consistent with mutation at this
locus: five families of differing ethnic backgrounds were homozygous by
descent for markers close to the KVLQT1 gene and a further three families
from the same geographical region were shown to be homozygous for a common
haplotype and to have the same homozygous mutation of the KVLQT1 gene.
However, analysis of a single small consanguineous family excluded linkage
to the KVLQT1 gene, establishing genetic heterogeneity in JLNS. The
affected children in this family were homozygous by descent for markers on
chromosome 21, in a region containing the gene IsK . This codes for a
transmembrane protein known to associate with KVLQT1 to form the slow
component of the delayed rectifier potassium channel. Sequencing of the
affected boys showed a homozygous mutation, demonstrating that mutation in
the IsK gene may be a rare cause of JLNS and that an indistinguishable
phenotype can arise from mutations in either of the two interacting
molecules.
ARTICLES
IsK and KvLQT1: mutation in either of the two subunits of the slow component of the delayed rectifier potassium channel can cause Jervell and Lange-Nielsen syndrome
Unit of Clinical Genetics, Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust, UCL Medical School, 30 Guilford Street, London WC1N 1EH, UK.
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