Alternative Splicing: Role of Pseudoexons in Human Genetic Disease

Abstract

In the pre‐mRNA splicing field the term ‘pseudoexons’ has been introduced to describe all those sequences usually localised deep in intronic regions that resemble real exons in appearance but are ignored by the spliceosomal machinery. Although we now know that some of these sequences are important for regulatory purposes it is also true that aberrant pseudoexon activation is increasingly described as one of the major causes of human disease. Several recent studies on pseudoexon inclusion–exclusion mechanisms have allowed researchers to gain further insight with regards to the mechanism that the spliceosome uses to discriminate between true and false exons during the normal splicing process. Most importantly, the newly gained knowledge regarding pseudoexon biology has been extensively exploited to devise novel therapeutic strategies aimed at inhibiting their inclusion in human patients. Key Concepts: Pseudoexons (also known as ‘false exons’) are very abundant in all eukaryotic genes, especially those harbouring long intronic sequences. In normal conditions, pseudoexon inclusion in mature mRNAs is efficiently inhibited. Mutational events that activate aberrant pseudoexon inclusion are a common source of disease‐causing mutations in humans. A variety of novel therapeutic approaches principally based on antisense oligonucleotide (AON) technology is currently being developed to inhibit their inclusion in human patients.