To splice or not to splice: pseudoexons in neurological disease and opportunities for intervention

Sue Fletcher¹,²,^*, Niall P Keegan¹,^*, Rita Mejzini¹,³ and Ianthe L Pitout¹

¹ Personalised Medicine Centre, Health Futures Institute, Murdoch University, 90 South St, Murdoch, WA 6150, Australia

² The University of Western Australia Medical School, Perth, WA 6009, Australia

³ Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia

Accurate exon selection and processing of pre-messenger RNA are crucial for normal gene expression. Mutations that alter splicing disrupt pre-mRNA processing and can have diverse effects on transcript structure, making the consequences of many such mutations difficult to predict. While next-generation sequencing technologies have transformed genetic diagnosis for many patients, deep intronic variants generally evade detection and characterisation. Of all the known types of splicing mutations, the most elusive to predict are those that activate pseudoexons. Because transcripts that contain pseudoexons are otherwise generally intact, exclusion (or ‘skipping’) of the pseudoexon during processing of the pre-mRNA is likely to generate a normal, functional mRNA. Characterisation of pseudoexon mutations will open opportunities for the development of antisense oligonucleotide strategies to overcome these disease-causing mutations.