Comprehensive Profiling of RBM20-Regulated CaMKIIδ Splice Variants Across the Heart, Skeletal Muscle, and Olfactory Bulbs

Abstract Calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ), encoded by the Camk2d gene, plays key regulatory roles in various Ca 2+ -regulated cellular processes. Extensive alternative splicing of the Camk2d gene generates multiple CaMKIIδ splice variants that exhibit differential roles. Despite significant advances in understanding the functions of CaMKIIδ, the full repertoire of Camk2d splice variants in a variety of tissues and their distinct roles in physiological and pathological contexts remain incompletely characterized due to the complex nature of multiple alternative splicing events in a single gene. Here, we conducted long-read amplicon sequencing to comprehensively investigate the murine Camk2d splice variants in the heart, skeletal muscle, and olfactory bulbs and show that Camk2d mRNAs in the heart and skeletal muscle have shorter 3’UTRs. We also demonstrate that a key regulator of Camk2d splicing, RNA-binding motif protein 20 (RBM20), whose gain-of-function mutations cause dilated cardiomyopathy, is crucial for the expression of heart-specific splice variants. Olfactory bulbs specifically express novel splice variants that utilize a mutually exclusive exon 6B and/or an alternative polyadenylation site in a novel exon 17.5. The tissue-specific repertoire of CaMKIIδ splice variants and their aberrant expression in disease model animals will help in understanding their roles in physiological and pathological contexts.