A spectrum of functional effects for disease causing mutations in the Jervell and Lange-Nielsen syndrome

Objective: Jervell and Lange-Nielsen syndrome (JLNS) is a recessively inher ited long QT syndrome (LQTS) characterised by profound sensorineural deafne ss and predisposition to syncope and sudden cardiac death. Mutation analysi s has established the presence of mutations in affected individuals in the genes KCNQ1 and KCNE1: the potassium channel complex responsible for the ca rdiac I-Ks current involved in repolarisation of the ventricular action pot ential. Our objective was to determine the functional effects of disease ca using mutations in JLNS. Methods: In this study we have investigated the el ectrophysiological effects of eight distinct JLNS mutations after expressio n of cRNA in Xenopus laevis oocytes. Results: KCNE1 mutant T59P/L60P showed no dominant negative effect and was a pure loss of function mutation. KCNQ 1 mutant E261D showed a strong dominant-negative effect. KCNQ1 mutant R243H produced a moderate dominant-negative effect, right shifted the steady-sta te activation curve and led to an increased deactivation rate. The behaviou r of KCNQ1 mutants 572-576del, 1008delC, R518X, Q530X, R594Q depended on th e relative quantities of mutant and wild-type proteins (with a weak dominan t-negative effect present at 1:3 but not 1:1 injection ratios). These data indicate the presence of an additional assembly domain before S2-S3 and the importance of the S4-S5 region in channel function and gating. Conclusions : Our data suggest a spectrum of behaviour for disease causing mutations fr om simple loss of function through to prominent dominant negative behaviour . (C) 2001 Elsevier Science B.V. All rights reserved.