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http://purl.uniprot.org/citations/18616619http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/18616619http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/18616619http://www.w3.org/2000/01/rdf-schema#comment"

Aim

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.

Conclusion

Clinical consequences of the novel R878C mutation correlate with results of physiological studies."xsd:string
http://purl.uniprot.org/citations/18616619http://purl.org/dc/terms/identifier"doi:10.1111/j.1748-1716.2008.01883.x"xsd:string
http://purl.uniprot.org/citations/18616619http://purl.org/dc/terms/identifier"doi:10.1111/j.1748-1716.2008.01883.x"xsd:string
http://purl.uniprot.org/citations/18616619http://purl.uniprot.org/core/author"Gui J."xsd:string
http://purl.uniprot.org/citations/18616619http://purl.uniprot.org/core/author"Gui J."xsd:string
http://purl.uniprot.org/citations/18616619http://purl.uniprot.org/core/author"Lei M."xsd:string
http://purl.uniprot.org/citations/18616619http://purl.uniprot.org/core/author"Lei M."xsd:string
http://purl.uniprot.org/citations/18616619http://purl.uniprot.org/core/author"Huang C."xsd:string
http://purl.uniprot.org/citations/18616619http://purl.uniprot.org/core/author"Huang C."xsd:string
http://purl.uniprot.org/citations/18616619http://purl.uniprot.org/core/author"Shi R."xsd:string
http://purl.uniprot.org/citations/18616619http://purl.uniprot.org/core/author"Shi R."xsd:string
http://purl.uniprot.org/citations/18616619http://purl.uniprot.org/core/author"Zhang Y."xsd:string
http://purl.uniprot.org/citations/18616619http://purl.uniprot.org/core/author"Zhang Y."xsd:string
http://purl.uniprot.org/citations/18616619http://purl.uniprot.org/core/author"Zhou X."xsd:string
http://purl.uniprot.org/citations/18616619http://purl.uniprot.org/core/author"Zhou X."xsd:string
http://purl.uniprot.org/citations/18616619http://purl.uniprot.org/core/author"Zhang H."xsd:string
http://purl.uniprot.org/citations/18616619http://purl.uniprot.org/core/author"Zhang H."xsd:string
http://purl.uniprot.org/citations/18616619http://purl.uniprot.org/core/author"Wang T."xsd:string
http://purl.uniprot.org/citations/18616619http://purl.uniprot.org/core/author"Wang T."xsd:string
http://purl.uniprot.org/citations/18616619http://purl.uniprot.org/core/author"Wan H."xsd:string
http://purl.uniprot.org/citations/18616619http://purl.uniprot.org/core/author"Wan H."xsd:string
http://purl.uniprot.org/citations/18616619http://purl.uniprot.org/core/author"Ma A."xsd:string
http://purl.uniprot.org/citations/18616619http://purl.uniprot.org/core/author"Ma A."xsd:string
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