Understanding the mechanistic and functional consequences of splicing factor mutations

Abstract

RNA splicing is a highly conserved eukaryotic process by which a precursor mRNA is converted into a mature mRNA. Precise regulation of RNA splicing is essential for proper cell development and maintenance. Disruption of RNA splicing is frequently associated with disease. Recent studies identified mutations in genes encoding RNA splicing factors in clonal hematopoiesis and diverse neoplastic diseases. The majority of spliceosomal mutations affect hotspot residues, while a subset of patients carry mutations in non-hotspot residues. Studies have demonstrated that some hotspot spliceosomal mutations result in splicing changes that promote disease; however, it is still unclear how remaining hotspot and non-hotspot spliceosomal mutations promote disease. To address this, I performed RNA-seq and quantified splicing dysregulation in isogenic cell lines and primary patient materials carrying splicing factor mutations. I identified 11 rare mutations in splicing factors SRSF2 and U2AF1 with likely disease pathogenicity, as well as two mis-spliced events with disease relevance driven by a hotspot mutation in SF3B1.