HsaEX0056568 @ hg19

Mutually exclusive exons 18A (HsaEX0056569) and 18N (HsaEX0056568) determine whether a functional 18A+ Scn8a mRNA is produced. Inclusion of 18N introduces a premature termination codon and leads to nonsense-mediated decay, whereas skipping both 18A and 18N produces an isoform that lacks large portions of the third and fourth transmembrane domains.

The 18N exon (neonatal form)(contains HsaEX0056568) has a stop codon in phase and although the mRNA can be detected by amplification methods, the truncated protein has not been observed. The switch from 18N to 18A (adult form)(contains HsaEX0056569) occurs only in a restricted set of neural tissues producing the functional channel while other tissues display the mRNA with the 18N exon also in adulthood. The mRNA species carrying the stop codon is subjected to Nonsense-Mediated Decay, providing a control mechanism of channel expression. The authors also map a string of cis-elements within the mutually exclusive exons and in the flanking introns responsible for their strict tissue and temporal specificity. These elements bind a series of positive (RbFox-1, SRSF1, SRSF2) and negative (hnRNPA1, PTB, hnRNPA2/B1, hnRNPD-like JKTBP) splicing regulatory proteins. These splicing factors, with the exception of RbFox-1, are ubiquitous but their levels vary during development and differentiation, ensuing unique sets of tissue and temporal levels of splicing factors.

Transcripts containing exon 18N (HsaEX0056568) have a conserved in-frame stop codon that predicts the synthesis of a truncated, two-domain protein similar to the fetal form of the muscle calcium channel. They appear to be degraded by nonsense-mediated decay in HEK cells.