HsaEX0056556 @ hg38

Negative results. Nine Nav1.5 (SCN5A) splice variants are known. Four of them, namely Nav1.5a, Nav1.5c, Nav1.5d, and Nav1.5e, generate functional channels in heterologous expression systems. In the present study, the authors systematically investigated electrophysiological properties of mutant T1620K channels in the background of all known functional Nav1.5 splice variants in HEK293 cells. This mutation is associated with two cardiac excitation disorders: long QT syndrome type 3 (LQT3) and isolated cardiac conduction disease (CCD). When investigating the effect of the T1620K mutation, the authors noticed similar channel defects in the background of hNav1.5, hNav1.5a, and hNav1.5c. In contrast, the hNav1.5d background produced differential effects: In the mutant channel, some gain-of-function features did not emerge, whereas loss-of-function became more pronounced. In case of hNav1.5e, the neonatal variant of hNav1.5, both the splice variant itself as well as the corresponding mutant channel showed electrophysiological properties that were distinct from the wild-type and mutant reference channels, hNav1.5 and T1620K, respectively. In conclusion, these data show that alternative splicing is a mechanism capable of generating a variety of functionally distinct wild-type and mutant hNav1.5 channels. Thus, the cellular splicing machinery is a potential player affecting genotype-phenotype correlations in SCN5A channelopathies. (About variants: Variant a and c differs from the canonical variant by skipping exon 18 (HsaEX0056556), and including Q1077 (HsaALTA0007521-2/2), respectively. Negative results for those. Variant D seems to use alternative splice sites in exon 17 (not in VastDB), and variant E uses the neonatal version of the ME exon (HsaEX0056558), while the other variants use the adult version (HsaEX0056559)).