TY - JOUR

T1 - Functional assessment of compound mutations in the KCNQ1 and KCNH2 genes associated with long QT syndrome.

AU - Grunnet, Morten

AU - Behr, Elijah Raphael

AU - Calloe, Kirstine

AU - Hofman-Bang, Jacob

AU - Till, Jan

AU - Christiansen, Michael

AU - McKenna, William John

AU - Olesen, Søren-Peter

AU - Schmitt, Nicole

N1 - Keywords: Alleles; DNA; Electrophysiology; Ether-A-Go-Go Potassium Channels; Female; Genetic Predisposition to Disease; Genotype; Heart Rate; Humans; KCNQ1 Potassium Channel; Long QT Syndrome; Male; Middle Aged; Mutation, Missense; Pedigree; Phenotype; Polymerase Chain Reaction

PY - 2005

Y1 - 2005

N2 - 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.

AB - 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.

U2 - 10.1016/j.hrthm.2005.07.025

DO - 10.1016/j.hrthm.2005.07.025

M3 - Journal article

C2 - 16253915

VL - 2

SP - 1238

EP - 1249

JO - Heart Rhythm

JF - Heart Rhythm

SN - 1547-5271

IS - 11

ER -