Faulty RNA splicing: consequences and therapeutic opportunities in brain and muscle disorders

Alternative splicing is a powerful mechanism that largely expands the coding potential of eukaryotic genomes. Indeed, its complex and flexible regulation is exploited by cells to adapt to various environmental conditions, through production of protein variants displaying different functions. Such flexibility, however, is accompanied by high risk of errors, and dysregulation of splicing is now recognized as an important factor in human diseases. Notably, the RNA-based nature of splicing, which involves high specificity through base pair recognition, offers a remarkable therapeutic opportunity by allowing design of tools with elevated target selectivity. Herein, we illustrate examples of how defective splicing, obtained by mutations affecting multiple layers of regulation, can result in pathology. In particular, we focus on splicing-related defects occurring in brain and muscle diseases and describe therapeutic approaches currently available for these pathologies.