Alternative splicing factors and cardiac disease: more than just mis-splicing?

Alternative splicing (AS) is the process wherein the exons from a single gene are joined in different combinations to produce nonidentical, albeit related, RNA transcripts. This process is important for the development and physiological function of many organs and is particularly important in the heart. Notably, AS has been implicated in cardiac disease and failure, and a growing number of genetic variants in AS factors have been identified in association with cardiac malformation and/or disease. With the field poised to interrogate how these variants affect cardiac development and disease, an understandable point of emphasis will undoubtedly be on downstream target gene mis-splicing. In this perspective article, we would like to encourage consideration not only of the potential for novel disease mechanisms, but also for contributions from disruption of the ever-expanding list of non-splicing functions ascribed to many AS factors. We discuss the emergence of a novel cardiac disease mechanism based on pathogenic RNA granules and speculate on the generality of such a mechanism among localization-disrupting AS factor genetic variants. We also highlight emerging non-splicing functions attributed to several AS factors with cardiac disease-associated genetic variants in the hopes of pointing to avenues for exploration of mechanisms that may contribute to disease alongside target gene mis-splicing.