Variations of intronic branchpoint motif: identification and functional implications in splicing and disease

The branchpoint (BP) motif is an essential intronic element for spliceosomal pre-mRNA splicing. In mammals, its sequence composition, distance to the downstream exon, and number of BPs per 3´ splice site are highly variable, unlike the GT/AG dinucleotides at the intron ends. These variations appear to provide evolutionary advantages for fostering alternative splicing, satisfying more diverse cellular contexts, and promoting resilience to genetic changes, thus contributing to an extra layer of complexity for gene regulation. Importantly, variants in the BP motif itself or in genes encoding BP-interacting factors cause human genetic diseases or cancers, highlighting the critical function of BP motif and the need to precisely identify functional BPs for faithful interpretation of their roles in splicing. In this perspective, we will succinctly summarize the major findings related to BP motif variations, discuss the relevant issues/challenges, and provide our insights.