{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T09:03:00Z","timestamp":1791018180490,"version":"4.1.0"},"reference-count":29,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2010,4,6]],"date-time":"2010-04-06T00:00:00Z","timestamp":1270512000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cardiovasc electrophysiol"],"published-print":{"date-parts":[[2010,5]]},"abstract":"<jats:p> <jats:bold>Effects of H558R on SSS\u2010Related Mutant Channels.\u2002<jats:italic>Introduction:<\/jats:italic><\/jats:bold> Mutations in <jats:italic>SCN5A,<\/jats:italic> the gene encoding \u03b1 subunit of cardiac type sodium channel, Na<jats:sub>v<\/jats:sub>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\u2013phenotype relationships have not been well addressed. One of the important contributors to such relationships is the genetic background such as single\u2010nucleotide polymorphisms.<\/jats:p><jats:p> <jats:bold>\n            <jats:italic>Methods and Results:<\/jats:italic>\n          <\/jats:bold> To clarify the effects of a common polymorphism in <jats:italic>SCN5A<\/jats:italic> gene, H558R, on <jats:italic>SCN5A<\/jats:italic>\u2010related SSS phenotype, we investigated the electrophysiological properties of all of the 13 known SSS\u2010related hNa<jats:sub>v<\/jats:sub>1.5 mutant channels on both H558 and R558 background. Electrophysiological properties of hNa<jats:sub>v<\/jats:sub>1.5 mutant channels were investigated by the whole\u2010cell 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\u2010targeted mutant channels. Loss\u2010of\u2010function defect of D1275N in <jats:italic>SCN5A<\/jats:italic> was rescued by R558 through enhancing cell surface targeting and improving steady\u2010state 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\u2010state availability of mutant channels. The electrophysiological properties of the remaining SSS\u2010related hNa<jats:sub>v<\/jats:sub>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.<\/jats:p><jats:p> <jats:bold>\n            <jats:italic>Conclusion:<\/jats:italic>\n          <\/jats:bold> We conclude that polymorphism H558R has mutation\u2010specific effects on <jats:italic>SCN5A<\/jats:italic>\u2010related SSS. Our data highlight the importance of common genetic variants in modulating phenotypes of genetic diseases. <jats:italic>(J Cardiovasc Electrophysiol, Vol. 21, pp. 564\u2010573, May 2010)<\/jats:italic><\/jats:p>","DOI":"10.1111\/j.1540-8167.2010.01762.x","type":"journal-article","created":{"date-parts":[[2010,4,7]],"date-time":"2010-04-07T04:29:54Z","timestamp":1270614594000},"page":"564-573","source":"Crossref","is-referenced-by-count":33,"title":["Mutation\u2010Specific Effects of Polymorphism H558R in <i>SCN5A<\/i>\u2010Related Sick Sinus 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