Abstract
Since the discovery of RNA splicing more than 40 years ago, our comprehension of the molecular events orchestrating constitutive and alternative splicing has greatly improved. Dysregulation of pre-mRNA splicing has been observed in many human diseases including neurodegenerative diseases and cancer. The recent identification of frequent somatic mutations in core components of the spliceosome in myeloid malignancies and functional analysis using model systems has advanced our knowledge of how splicing alterations contribute to disease pathogenesis. In this review, we summarize our current understanding on the mechanisms of how mutant splicing factors impact splicing and the resulting functional and pathophysiological consequences. We also review recent advances to develop novel therapeutic approaches targeting splicing catalysis and splicing regulatory proteins, and discuss emerging technologies using oligonucleotide-based therapies to modulate pathogenically spliced isoforms.