Human Molecular Genetics, Vol 5, 1319-1324, Copyright © 1996 by Oxford University Press
MW Russell, M Dick 2nd, FS Collins and LC Brody
Congenital long QT syndrome (LQTS) is a heterogeneous group of heritable
disorders characterized by prolongation of the QT interval on the
electrocardiogram, ventricular arrhythmias and sudden death. At least four
genes can, when mutated, produce this phenotype. Of these genes, the
recently identified KVLQT1 potassium channel is thought to be the one most
commonly responsible. In this study, we used single strand conformational
polymorphism (SSCP) analysis to screen two large and nine small LQTS
families for mutations of the KVLQT1 potassium channel gene. We identified
a novel missense mutation in two unrelated families which substitutes a
serine for a conserved glycine in the putative pore region of the KVLQT1
channel. In a third family, a new alanine to valine mutation at a CpG
dinucleotide resulted in the spontaneous occurrence of the long QT syndrome
in monozygotic twin offspring of unaffected parents. Mutations at this same
nucleotide have been observed in eight of the 19 LQTS families determined
to have KVLQT1 mutations, suggesting this is a mutational hot spot. Both of
these mutations alter the amino acid sequence in, or adjacent to, the pore
of the channel and many diminish the channel's ability to conduct a
repolarizing potassium current. To date, all KVLQT1 mutations determined to
cause the LQTS are missense mutations. These data confirm the role of
KVLQT1 in the LQTS and suggest that mutant KVLQT1 proteins may exert a
dominant negative effect on repolarizing potassium currents by forming
multimers with normal potassium channel protein subunits, dramatically
reducing the number of fully-functional KVLQT1 channels.
ARTICLES
KVLQT1 mutations in three families with familial or sporadic long QT syndrome
Division of Pediatric Cardiology, University of Michigan, C.S. Mott Children's Hospital, Ann Arbor 48109-0204, USA.
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