Faculty Collaboration Database

Novel missense mutation in the cyclic nucleotide-binding domain of HERG causes long QT syndrome. Am J Med Genet 1996 Oct 02;65(1):27-35

Date

10/02/1996

Pubmed ID

8914737

DOI

10.1002/(SICI)1096-8628(19961002)65:1<27::AID-AJMG4>3.0.CO;2-V

Scopus ID

2-s2.0-0029793031 (requires institutional sign-in at Scopus site)   57 Citations

Abstract

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.

Author List

Satler CA, Walsh EP, Vesely MR, Plummer MH, Ginsburg GS, Jacob HJ

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Amino Acid Sequence
Binding Sites
Cation Transport Proteins
Chromosome Mapping
Chromosomes, Human, Pair 7
DNA-Binding Proteins
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels
Female
Genetic Linkage
Humans
Long QT Syndrome
Male
Middle Aged
Molecular Sequence Data
Mutation
Nucleotides, Cyclic
Pedigree
Polymorphism, Single-Stranded Conformational
Potassium Channels
Potassium Channels, Voltage-Gated
Protein Conformation
Trans-Activators
Transcriptional Regulator ERG