Developments in RNA splicing and disease

Pre-mRNA processing, including 50-end capping, splicing, editing, and polyadenylation, consists of a series of orchestrated and primarily cotranscriptional steps that ensure both the high fidelity and extreme diversity characteristic of eukaryotic gene expression. Alternative splicing and editing allow relatively small genomes to encode vast proteomic arrays while alternative 30-end formation enables variations in mRNA localization, translation, and stability. Of course, this mechanistic complexity comes at a high price. Mutations in the myriad of RNA sequence elements that regulate mRNA biogenesis, as well as the trans-acting factors that act upon these sequences, underlie a number of human diseases. In this review, we focus on one of these key RNA processing steps, splicing, to highlight recent studies that describe both conventional and novel pathogenic mechan-isms that underlie muscle and neurological diseases. Deep sequencing and microarray analyses ofthe human transcriptome have revealed that.90 % of our genes undergo alternative splicing, which permits a limited genome to encode the vast proteomic repertoire require