Splicing in disease: disruption of the splicing code and the decoding machinery

Abstract

Cis-acting elements within exons and introns make up a splicing code that is required for efficient pre-mRNA splicing. A large fraction of non-synonymous exonic mutations cause disease due to disrupted splicing rather than the predicted amino-acid change. Splicing affects disease by three general mechanisms: as a direct cause, as a modifier of severity and as a determinant of disease susceptibility. In all three cases, the pathogenic splicing effect can be in cis affecting the 'disease gene' or in trans resulting from alterations of the splicing environment. Genome-wide analysis of alternative splicing using splicing microarrays has identified coordinated networks of splicing regulation. Computational analysis of co-regulated exons has identified motifs of known RNA binding proteins as well as novel motifs. Pathogenesis of a growing number of microsatellite expansion disorders is known to involve the expression of repeat-containing RNAs that have a toxic effect by disrupting regulators of alternative splicing. Analysis of 50 cancer-relevant genes that are thought to be well characterized has found that two-thirds of these genes express novel isoforms in normal tissues, and that the novel isoform is predominant for 40% of these genes. This finding illustrates the need to identify predominant splice variants for the cells and tissues of interest. The oncogenic activities of two genes are enhanced by the splicing factor SF2/ASF through induction of oncogenic alternatively spliced isoforms. Splicing-based therapeutic approaches are directed at either reversing or circumventing the deleterious splicing pattern.