title: A spectrum of functional effects for disease causing mutations in the Jervell and Lange-Nielsen syndrome.
abstract: OBJECTIVE
  Jervell and Lange-Nielsen syndrome (JLNS) is a recessively inherited long QT syndrome (LQTS) characterised by profound sensorineural deafness and predisposition to syncope and sudden cardiac death. Mutation analysis has established the presence of mutations in affected individuals in the genes KCNQ1 and KCNE1: the potassium channel complex responsible for the cardiac I(Ks) current involved in repolarisation of the ventricular action potential. Our objective was to determine the functional effects of disease causing mutations in JLNS.
  
  
  METHODS
  In this study we have investigated the electrophysiological effects of eight distinct JLNS mutations after expression of cRNA in Xenopus laevis oocytes.
  
  
  RESULTS
  KCNE1 mutant T59P/L60P showed no dominant negative effect and was a pure loss of function mutation. KCNQ1 mutant E261D showed a strong dominant-negative effect. KCNQ1 mutant R243H produced a moderate dominant-negative effect, right shifted the steady-state activation curve and led to an increased deactivation rate. The behaviour of KCNQ1 mutants 572-576del, 1008delC, R518X, Q530X, R594Q depended on the relative quantities of mutant and wild-type proteins (with a weak dominant-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 from simple loss of function through to prominent dominant negative behaviour.
authors.affiliation: Centre for Clinical Pharmacology, Department of Medicine, University College London, The Rayne Institute, 5 University Street, London WC1E 6JJ, UK.
authors.forename: L
authors.initials: L
authors.lastname: Huang
authors.forename: M
authors.initials: M
authors.lastname: Bitner-Glindzicz
authors.forename: L
authors.initials: L
authors.lastname: Tranebjaerg
authors.forename: A
authors.initials: A
authors.lastname: Tinker
mesh_terms: D000818:Animals; D005260:Female; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D015640:Ion Channel Gating; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D014982:Xenopus laevis
chemical_list: D015221:Potassium Channels; D020033:Protein Isoforms