Novel missense mutation in the cyclic nucleotide-binding domain of HERG causes long QT syndrome
- Beth Israel Hospital, Boston, MA (United States); and others
Autosomal-dominant long QT syndrome (LQT) is an inherited disorder, predisposing affected individuals to sudden death from tachyarrhythmias. To identify the gene(s) responsible for LQT, we identified and characterized an LQT family consisting of 48 individuals. DNA was screened with 150 microsatellite polymorphic markers encompassing approximately 70% of the genome. We found evidence for linkage of the LQT phenotype to chromosome 7(q35-36). Marker D7S636 yielded a maximum lod score of 6.93 at a recombination fraction ({theta}) of 0.00. Haplotype analysis further localized the LQT gene within a 6-2-cM interval. HERG encodes a potassium channel which has been mapped to this region. Single-strand conformational polymorphism analyses demonstrated aberrant bands that were unique to all affected individuals. DNA sequencing of the aberrant bands demonstrated a G to A substitution in all affected patients; this point mutation results in the substitution of a highly conserved valine residue with a methionine (V822M) in the cyclic nucleotide-binding domain of this potassium channel. The cosegregation of this distinct mutation with LQT demonstrates that HERG is the LQT gene in this pedigree. Furthermore, the location and character of this mutation suggests that the cyclic nucleotide-binding domain of the potassium channel encoded by HERG plays an important role in normal cardiac repolarization and may decrease susceptibility to ventricular tachyarrhythmias. 38 refs., 7 figs., 2 tabs.
- OSTI ID:
- 539198
- Journal Information:
- American Journal of Medical Genetics, Vol. 65, Issue 1; Other Information: PBD: 2 Oct 1996
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
BASIC STUDIES
PATIENTS
CARDIOVASCULAR DISEASES
PHENOTYPE
GENOTYPE
DEATH
RISK ASSESSMENT
GENES
GENE MUTATIONS
GENETIC MAPPING
DNA SEQUENCING
HUMAN CHROMOSOME 7
PORINS
NUCLEOTIDES
STATISTICS
DOMINANT MUTATIONS
GENETICS
BIOLOGICAL MARKERS
BANDING TECHNIQUES
AMINO ACID SEQUENCE
POTASSIUM