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Titolo:
Characterization of a novel missense mutation in the pore of HERG in a patient with long QT Syndrome
Autore:
Yoshida, H; Horie, M; Otani, H; Takano, M; Tsuji, K; Kubota, T; Fukunami, M; Sasayama, S;
Indirizzi:
Kyoto Univ, Grad Sch Med, Dept Cardiovasc Med, Div Cardiac Electrophysiol,Kyoto 6068507, Japan Kyoto Univ Kyoto Japan 6068507 rdiac Electrophysiol,Kyoto 6068507, Japan Kyoto Univ, Grad Sch Med, Dept Physiol & Biophys, Kyoto 606, Japan Kyoto Univ Kyoto Japan 606 Med, Dept Physiol & Biophys, Kyoto 606, Japan Osaka Prefecture Hosp, Div Cardiol, Osaka, Japan Osaka Prefecture Hosp Osaka Japan cture Hosp, Div Cardiol, Osaka, Japan
Titolo Testata:
JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY
fascicolo: 9, volume: 10, anno: 1999,
pagine: 1262 - 1270
SICI:
1045-3873(199909)10:9<1262:COANMM>2.0.ZU;2-9
Fonte:
ISI
Lingua:
ENG
Soggetto:
INHERITED CARDIAC-ARRHYTHMIA; RECTIFIER K+ CURRENT; POTASSIUM CHANNEL; MOLECULAR-BASIS; GENE; KVLQT1; FORM; K(V)LQT1; PROTEINS; REGION;
Keywords:
long QT syndrome; HERG; missense mutation; patch clamp recording;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
33
Recensione:
Indirizzi per estratti:
Indirizzo: Horie, M Kyoto Univ, Grad Sch Med, Dept Cardiovasc Med, Div Cardiac Electrophysiol,Kyoto 6068507, Japan Kyoto Univ Kyoto Japan 6068507 ctrophysiol,Kyoto 6068507, Japan
Citazione:
H. Yoshida et al., "Characterization of a novel missense mutation in the pore of HERG in a patient with long QT Syndrome", J CARD ELEC, 10(9), 1999, pp. 1262-1270

Abstract

HERG Mutation and Long QT Syndrome. Introduction: A new strategy to elucidate the molecular mechanisms underlying the long QT syndrome (LQTS) is now available with genetic mutational analyses and characterization of ion channel mutations. Methods and Results: In a 26-year-old woman with LQTS, we identified a novel missense mutation in the pore of HERG by using polymerase chain reaction/single-strand conformation polymorphism (PCR/SSCP) and sequencing of her genomic DNA. The mutation resulted in an amino acid substitution of a positively charged lysine for a highly conserved uncharged asparagine at codon 629 (N629K). Whole cell, patch clamp studies were conducted in COS7 cells by transfecting with wild-type (WT) and/or the mutant N629K HERG, The WT HERG produced an I-Kr-like, E-4031-sensitive conductance with an inward rectification, In contrast, the cells transfected with the N629K HERG did not display any time-dependent current. Cotransfection of WT and N629K HERG (at a ratio of 1:1) produced a significantly smaller conductance when compared withWT HERG (WT 59.9 +/- 7.3 pA/pF [n = 22] vs WT+N629K 5.5 +/- 2.3 pA/pF [n =11]; P < 0.01), but did not alter K+ ion selectivity and tail current-voltage dependence. Because aprindine hydrochloride was effective in preventingventricular tachycardias, we also tested the effect of the drug on WT HERG(I-Kr) and KvLQT1/KCNE1 (I-Ks) currents expressed in COS7. Conclusion: Functional analyses of a novel missense mutation in the pore of HERG suggest that the mutation causes marked reduction of I-Kr via a dominant negative effect.

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Documento generato il 31/03/20 alle ore 22:10:15