The psychiatric risk gene CACNA1C encodes distinct full-length isoforms in human brain, heart and aorta

Abstract CACNA1C is a risk gene for multiple psychiatric disorders and the Ca V 1.2 protein it encodes is a potential target for their treatment. It is known that alternative start exon usage and splicing of CACNA1C RNA results in multiple transcript isoforms. However, the identity of full-length isoforms, and their relative abundance between tissues, remains unknown. Such information is important for understanding the molecular mechanisms of illness associations and to advance the potential for Ca V 1.2 isoform-selective drugs. In this study we compared full-length isoforms expressed in human brain with those expressed in heart and aorta using PCR-targeted long-read nanopore amplicon sequencing. We also performed 5’-RACE to profile which CACNA1C transcription start exons are used. CACNA1C RNA splicing revealed distinct tissue-enriched isoforms in brain, heart and aorta, with the results corroborated by publicly available short-read RNA-seq data. For example, splicing of mutually exclusive exons 21 and 22 differentiated isoforms expressed in the brain from those in the heart and aorta. 5’-RACE identified a novel start exon, exon 1d, which was detected in brain and aorta but not heart, and which predicts channels with a truncated N-terminus. The full-length isoforms identified here, from both the previously known start exons and the novel start exon, are likely to impact on the function and the pharmacology of the encoded Ca V 1.2 channel. Identification of brain-enriched isoforms provides the possibility of designing drugs preferentially targeting Ca V 1.2 for psychiatric indications.