Referenced in: none

Automatically associated channels: Kv11.1 , Kv7.1

Title: A single hERG mutation underlying a spectrum of acquired and congenital long QT syndrome phenotypes.

Authors: J B Saenen, A D C Paulussen, R J Jongbloed, C L Marcelis, R A H J Gilissen, J Aerssens, D J Snyders, A L Raes

Journal, date & volume: J. Mol. Cell. Cardiol., 2007 Jul , 43, 63-72

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/17531263

Abstract
The long QT syndrome (LQTS) is a multi-factorial disorder that predisposes to life-threatening arrhythmias. Both hereditary and acquired subforms have been identified. Here, we present clinical and biophysical evidence that the hERG mutation c.1039 C>T (p.Pro347Ser or P347S) is responsible for both the acquired and the congenital phenotype. In one case the genotype remained silent for years until the administration of several QT-prolonging drugs resulted into a full-blown phenotype, that was reversible upon cessation of these compounds. On the other hand the mutation was responsible for a symptomatic congenital LQTS in a Dutch family, displaying a substantial heterogeneity of the clinical symptoms. Biophysical characterization of the p.Pro347Ser potassium channels using whole-cell patch clamp experiments revealed a novel pathogenic mechanism of reciprocal changes in the inactivation kinetics combined with a dominant-negative reduction of the functional expression in the heterozygous situation, yielding a modest genetic predisposition for LQTS. Our data show that in the context of the multi-factorial aetiology underlying LQTS a modest reduction of the repolarizing power can give rise to a spectrum of phenotypes originating from one mutation. This observation increases the complexity of genotype-phenotype correlations in more lenient manifestations of the disease and underscores the difficulty of predicting the expressivity of the LQTS especially for mutations with a more subtle impact such as p.Pro347Ser.