Arrhythmogenic biophysical phenotype for SCN5A mutation S1787N depends upon splice variant background and intracellular acidosis

Rou Mu Hu, Bi Hua Tan, David J. Tester, Chunhua Song, Yang He, Sinisa Dovat, Blaise Z. Peterson, Michael J. Ackerman, Jonathan C. Makielski

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Background: SCN5A is a susceptibility gene for type 3 long QT syndrome, Brugada syndrome, and sudden infant death syndrome. INa dysfunction from mutated SCN5A can depend upon the splice variant background in which it is expressed and also upon environmental factors such as acidosis. S1787N was reported previously as a LQT3-associated mutation and has also been observed in 1 of 295 healthy white controls. Here, we determined the in vitro biophysical phenotype of SCN5A-S1787N in an effort to further assess its possible pathogenicity. Methods and Results: We engineered S1787N in the two most common alternatively spliced SCN5A isoforms, the major isoform lacking a glutamine at position 1077 (Q1077del) and the minor isoform containing Q1077, and expressed these two engineered constructs in HEK293 cells for electrophysiological study. Macroscopic voltage-gated/Na was measured 24 hours after transfection with standard whole-cell patch clamp techniques. We applied intracellular solutions with pH7.4 or pH6.7. S1787N in the Q1077 background had WT-like /Na including peak /Na density, activation and inactivation parameters, and late /Na amplitude in both pH 7.4 and pH 6.7. However, with S1787N in the Q1077del background, the percentages of /Na late/peak were increased by 2.1 fold in pH 7.4 and by 2.9 fold in pH 6.7 when compared to WT. Conclusion: The LQT3-like biophysical phenotype for S1787N depends on both the SCN5A splice variant and on the intracellular pH. These findings provide further evidence that the splice variant and environmental factors affect the molecular phenotype of cardiac SCN5A-encoded sodium channel (Nav1.5), has implications for the clinical phenotype, and may provide insight into acidosis-induced arrhythmia mechanisms.

Original languageEnglish (US)
Article numbere0124921
JournalPloS one
Issue number4
StatePublished - Apr 29 2015

All Science Journal Classification (ASJC) codes

  • General


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