Identification and functional characterization of a novel KCNE2 (MiRP1) mutation that alters HERG channel kinetics.
Long-QT syndrome (LQTS) may cause syncope and sudden death due to cardiac tachyarrhythmia. Chromosome 7-linked LQTS (LQT2) has been correlated with mutations in the human ether-a-go-go-related gene (HERG). HERG forms voltage-gated K channels that may be associated with Mink-related peptide 1 (MiRP1), an auxiliary beta-subunit. The channels mediate currents that resemble native I(Kr). Mutations in the KCNE2 gene encoding MiRP1 may also cause LQTS. In this study, the frequency of mutations in KCNE2 of 150 unrelated LQTS patients without known genotype and of 100 controls was analyzed using single-strand conformation polymorphism analysis and direct sequencing. We identified a novel missense mutation, V65 M, in the KCNE2 gene of a 17-year-old female with syncope and LQTS. Expression studies in Chinese hamster ovary cells revealed that mutant and wild-type MiRP1 co-localized with HERG subunits and formed functional channels. However, mutant HERG/MiRP1(V65M) channels mediated currents with an accelerated inactivation time course compared with wild-type channels. The accelerated inactivation time course of HERG/MiRP1(V65M) channels may decrease I(Kr) current density of myocardial cells, thereby impairing the ability of myocytes to repolarize in response to sudden membrane depolarizations such as extrasystoles.
Institute for Neural Signal Transduction, Centre for Molecular Neurobiology Hamburg, University of Hamburg, Martinistrasse 52, 20246 Hamburg, Germany. isbrandt@uni-hamburg.de
Dirk
D
Isbrandt
Patrick
P
Friederich
Anna
A
Solth
Wilhelm
W
Haverkamp
Andreas
A
Ebneth
Martin
M
Borggrefe
Harald
H
Funke
Kathrin
K
Sauter
Günter
G
Breithardt
Olaf
O
Pongs
Eric
E
Schulze-Bahr
D000818:Animals; D016466:CHO Cells; D027682:Cation Transport Proteins; D006224:Cricetinae; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004558:Electric Stimulation; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D005838:Genotype; D006801:Humans; D008133:Long QT Syndrome / Q000151:congenital / Q000235:genetics*; D020125:Mutation, Missense; D015221:Potassium Channels / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D013347:Subcellular Fractions; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C059983:potassium channel protein I(sk)