Functional assessment of compound mutations in the KCNQ1 and KCNH2 genes associated with long QT syndrome
Received 20 April 2005; accepted 25 July 2005. published online 08 August 2005.
Background
Long QT syndrome (LQTS) is a cardiovascular disorder characterized by prolonged QTc time, syncope, or sudden death caused by torsades de pointes and ventricular fibrillation. We investigated the clinical and electrophysiologic phenotype of individual mutations and the compound mutations in a family in which different genotypes could be found.
Objectives
The purpose of this study was to determine the impact of genotype-based diagnostic assessment in LQTS.
Methods
We used cascade screening and functional analyses to investigate the phenotype in a family with LQTS. The contributions of the compound mutations in the KCNQ1 and KCNH2 genes (KCNQ1 R591H, KCNH2 R328C) were analyzed by heterologous expression in Xenopus laevis oocytes using two-electrode voltage clamp and by confocal imaging.
Results
KCNH2 R328C did not show any functional phenotype whereas KCNQ1 R591H resulted in severe reduction of current. Neither wild-type nor mutant channels affected each other functionally in coexpression experiments. Therefore, a direct interaction between KCNQ1 and KCNH2 was ruled out under these conditions.
Conclusion
Assessment of novel mutational findings in LQTS should include accurate genetic and functional analysis. Notably, appropriate studies are needed if two or more mutations in different genes are present in one proband. Our findings prompt reconsideration of the impact of compound mutations in LQTS families and reinforce the need for thorough functional evaluation of novel ion channel mutations before assignment of pathogenic status.
gHeart Hospital & University College, London, United Kingdom
Address reprint requests and correspondence: Dr. Morten Grunnet, Department of Medical Physiology and Copenhagen Heart Arrhythmia Research Center, The Panum Institute, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark
This work was supported by The John and Birthe Meyer Foundation, The Velux Foundation, The NovoNordisk Foundation, The Danish Heart Foundation, and The Beckett Foundation.
ABSTRACT