title: Correlations between clinical and physiological consequences of the novel mutation R878C in a highly conserved pore residue in the cardiac Na+ channel.
abstract: OBJECTIVE
  We compared the clinical and physiological consequences of the novel mutation R878C in a highly conserved pore residue in domain II (S5-S6) of human, hNa(v)1.5, cardiac Na(+) channels.
  
  
  METHODS
  Full clinical evaluation of pedigree members through three generations of a Chinese family combined with SCN5A sequencing from genomic DNA was compared with patch and voltage-clamp results from two independent expression systems.
  
  
  RESULTS
  The four mutation carriers showed bradycardia, and slowed sino-atrial, atrioventricular and intraventricular conduction. Two also showed sick sinus syndrome; two had ST elevation in leads V1 and V2. Unlike WT-hNa(v)1.5, whole-cell patch-clamped HEK293 cells expressing R878C-hNa(v)1.5 showed no detectable Na(+) currents (i(Na)), even with substitution of a similarly charged lysine residue. Voltage-clamped Xenopus oocytes injected with either 0.04 or 1.5 microg microL(-1) R878C-hNa(v)1.5 cRNA similarly showed no i(Na), yet WT-hNa(v)1.5 cRNA diluted to 0.0004-0.0008 ng microL(-1)resulted in expression of detectable i(Na). i(Na) was simply determined by the amount of injected WT-hNa(v)1.5: doubling the dose of WT-hNa(v)1.5 cRNA doubled i(Na). i(Na) amplitudes and activation and inactivation characteristics were similar irrespective of whether WT-hNa(v)1.5 cRNA was given alone or combined with equal doses of R878C-hNa(v)1.5 cRNA therefore excluding dominant negative phenotypic effects. Na(+) channel function in HEK293 cells transfected with R878C-hNa(v)1.5 was not restored by exposure to mexiletine (200 microM) and lidocaine (100 microM). Fluorescence confocal microscopy using E3-Nav1.5 antibody demonstrated persistent membrane expression of both WT and R878C-hNa(v)1.5. Modelling studies confirmed that such i(Na) reductions reproduced the SSS phenotype.
  
  
  CONCLUSIONS
  Clinical consequences of the novel R878C mutation correlate with results of physiological studies.
authors.affiliation: Cardiovascular Ion Channel Disease Laboratory, Department of Paediatrics, First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.forename: A
authors.initials: A
authors.lastname: Ma
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.forename: J
authors.initials: J
authors.lastname: Gui
authors.forename: H
authors.initials: H
authors.lastname: Wan
authors.forename: R
authors.initials: R
authors.lastname: Shi
authors.forename: C
authors.initials: C
authors.lastname: Huang
authors.forename: A A
authors.initials: AA
authors.lastname: Grace
authors.forename: C L-H
authors.initials: CL
authors.lastname: Huang
authors.forename: D
authors.initials: D
authors.lastname: Trump
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: T
authors.initials: T
authors.lastname: Zimmer
authors.forename: M
authors.initials: M
authors.lastname: Lei
mesh_terms: D000328:Adult; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism; D004562:Electrocardiography; D005260:Female; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018613:Microscopy, Confocal; D009154:Mutation / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism*; D010375:Pedigree; D012804:Sick Sinus Syndrome / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics*; D014981:Xenopus
chemical_list: D015222:Sodium Channels