Genome-wide association studies (GWAS) have determined a surprising link between dysfunctional cardiac conduction and variants within SCN10A, which encodes nociceptor-associated sodium-gated ion channel subunit NaV1.8. Follow-up functional studies targeting NaV1.8 revealed only a minor contribution to cardiac physiology; therefore, it was unclear how SCN10A mutations promoted the development of cardiac conduction disease.
In this issue of the Journal of Clinical Investigation, the research groups of Vincent Christoffels, Marcelo Nobrega, Phil Barnett, and Ivan Moskowitz teamed up and have now revealed that a transcriptional enhancer within SCN10A is required for cardiac expression of SCN5A, encoding the sodium-gated ion channel subunit NaV1.5, which is critical for cardiac conduction. In humans, a variant in the enhancer within SCN10A was associated with slowed conduction, Brugada syndrome, and reduced SCN5A transcription.
In the accompanying Commentary, David Park and Glenn Fishman of the New York School of Medicine discuss how this study highlights the importance of functional studies to distinguish between coding and non-coding functions of genomic regions identified by GWAS.
JCI online ahead of print, March 18, 2014