Background:
Genetic variants in
SCN10A
, encoding the neural voltage-gated sodium channel NaV1.8, are strongly associated with atrial fibrillation, Brugada syndrome, cardiac conduction velocities and heart rate. The cardiac function of
SCN10A
has not been resolved, however, and diverging mechanisms have been proposed. Here, we investigated the cardiac expression of
SCN10A
and the function of a variant-sensitive intronic enhancer previously linked to the regulation of
SCN5A
, encoding the major essential cardiac sodium channel NaV1.5.
Methods:
The expression of
SCN10A
was investigated in mouse and human hearts. Using CRISPR/Cas9 genome editing, the mouse intronic enhancer was disrupted, and mutant mice were characterized by transcriptomic and electrophysiological analyses. The association of genetic variants at
SCN5A-SCN10A
enhancer regions and gene expression were evaluated by GWAS SNP mapping and expression QTL analysis.
Results:
We found that cardiomyocytes of the atria, sinoatrial node and ventricular conduction system express a short transcript comprising the last 7 exons of the gene (
Scn10a-short
). Transcription occurs from an intronic enhancer-promoter complex, while full length
Scn10a
transcript was undetectable in the human and mouse heart. Expression QTL analysis revealed that the genetic variants in linkage disequilibrium with genetic variant rs6801957 in the intronic enhancer associate with
SCN10A
transcript levels in the heart. Genetic modification of the enhancer in the mouse genome led to reduced cardiac
Scn10a-short
expression in atria and ventricles, reduced cardiac sodium current in atrial cardiomyocytes, atrial conduction slowing and arrhythmia, while expression of
Scn5a
, the presumed enhancer target gene, remained unaffected. In patch-clamp transfection experiments, expression of
Scn10a-short
-encoded NaV1.8-short increased NaV1.5-mediated sodium current. We propose that non-coding genetic variation modulates transcriptional regulation of
Scn10a-short
in cardiomyocytes that impacts on NaV1.5-mediated sodium current and heart rhythm.
Conclusions:
Genetic variants in and around
SCN10A
modulate enhancer function and expression of a cardiac-specific
SCN10A-short
transcript. We propose that non-coding genetic variation modulates transcriptional regulation of a functional C-terminal portion of NaV1.8 in cardiomyocytes that impacts on NaV1.5 function, cardiac conduction velocities and arrhythmia susceptibility.
Genetic variation in transcriptional regulation of wheat seed starch content and its conversion to bioethanol
