NOVEL MISSENSE MUTATION IN THE CYCLIC NUCLEOTIDE-BINDING DOMAIN OF HERG CAUSES LONG QT SYNDROME

Autosomal-dominant long QT syndrome (LQT) is an inherited disorder, pr edisposing affected individuals to sudden death from tachyarrhythmias. To identify the gene(s) responsible for LQT, we identified and charac terized an LQT family consisting of 48 individuals. DNA was screened w ith 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 f urther 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 aberra nt 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-bind ing domain of this potassium channel. The cosegregation of this distin ct mutation with LQT demonstrates that HERG is the LQT gene in this pe digree. Furthermore, the location and character of this mutation sugge sts that the cyclic nucleotide-binding domain of the potassium channel encoded by HERG plays an important role in normal cardiac repolarizat ion and may decrease susceptibility to ventricular tachyarrhythmias. ( C) 1996 Wiley-Liss, Inc.