Alternative splicing: role of pseudoexons in human disease and potential therapeutic strategies

What makes a nucleotide sequence an exon (or an intron) is a question that still lacks a satisfactory answer. Indeed, most eukaryotic genes are full of sequences that look like perfect exons, but which are nonetheless ignored by the splicing machinery (hence the name ‘pseudoexons’). The existence of these pseudoexons has been known since the earliest days of splicing research, but until recently the tendency has been to view them as an interesting, but rather rare, curiosity. In recent years, however, the importance of pseudoexons in regulating splicing processes has been steadily revalued. Even more importantly, clinically oriented screening studies that search for splicing mutations are beginning to uncover a situation where aberrant pseudoexon inclusion as a cause of human disease is more frequent than previously thought. Here we aim to provide a review of the mechanisms that lead to pseudoexon activation in human genes and how the various cis ‐ and trans ‐acting cellular factors regulate their inclusion. Moreover, we list the potential therapeutic approaches that are being tested with the aim of inhibiting their inclusion in the final mRNA molecules.