title: Mutation-specific effects of polymorphism H558R in SCN5A-related sick sinus syndrome.
abstract: BACKGROUND
  Mutations in SCN5A, the gene encoding alpha subunit of cardiac type sodium channel, Na(v)1.5, lead to familial sick sinus syndrome (SSS). Although several molecular mechanisms for this genetic condition have been explored, the underlying mechanisms for the variable genotype-phenotype relationships have not been well addressed. One of the important contributors to such relationships is the genetic background such as single-nucleotide polymorphisms.
  
  
  RESULTS
  To clarify the effects of a common polymorphism in SCN5A gene, H558R, on SCN5A-related SSS phenotype, we investigated the electrophysiological properties of all of the 13 known SSS-related hNa(v)1.5 mutant channels on both H558 and R558 background. Electrophysiological properties of hNa(v)1.5 mutant channels were investigated by the whole-cell patch clamp technique in HEK293 cells. When peak currents were affected by the mutation, cell surface biotinylation was performed to quantify the fraction of correctly cell membrane-targeted mutant channels. Loss-of-function defect of D1275N in SCN5A was rescued by R558 through enhancing cell surface targeting and improving steady-state activation of the mutant channels. In contrast, the defects of mutants E161K, P1298L, and R1632H were aggravated in the R558 background, mainly due to the reduced steady-state availability of mutant channels. The electrophysiological properties of the remaining SSS-related hNa(v)1.5 mutants including the missense mutants (L212P, T220I, DelF1617, T187I, R878C, G1408R), and the truncated mutants (W1421X, K1578fs/52, R1623X) were not significantly affected by H558R.
  
  
  CONCLUSIONS
  We conclude that polymorphism H558R has mutation-specific effects on SCN5A-related SSS. Our data highlight the importance of common genetic variants in modulating phenotypes of genetic diseases.
authors.affiliation: Cardiovascular Research Group, School of Clinical and Laboratory Sciences, University of Manchester, Manchester, UK.
authors.forename: Junhong
authors.initials: J
authors.lastname: Gui
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Dorothy
authors.initials: D
authors.lastname: Trump
authors.forename: Thomas
authors.initials: T
authors.lastname: Zimmer
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
mesh_terms: D019921:Biotinylation; D015153:Blotting, Western; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology / Q000648:ultrastructure; D004247:DNA / Q000235:genetics; D004274:DNA, Recombinant / Q000235:genetics; D004594:Electrophysiology; D006801:Humans; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012804:Sick Sinus Syndrome / Q000235:genetics*; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D004274:DNA, Recombinant; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D004247:DNA