Alternative Splicing and Human Disease

Abstract

Almost all human protein coding genes undergo alternative splicing, and an increasing number of diseases is associated with the selection of ‘wrong’ splice sites. Alternative missplicing can be caused by deoxyribonucleic acid point mutations, changes in repetitive sequences or alterations in proteins that regulate splicing. The effect of these mutations can be evaluated by bioinformatic means, but these predictions need to be verified experimentally. With the exception of premature stop codons that are introduced by aberrantly spliced exons, the mechanism of pathological exon usage that leads to a disease is generally poorly understood. A pathological change in the activity of splicing factors typically results in numerous small changes in exon usage. Numerous screening efforts identified oligonucleotides and small molecular weight substances that can be tested as therapeutic approaches for diseases caused by missplicing. Key Concepts: Alternative splice site selection is regulated by combinatorial control through a network of protein–protein, protein–RNA and RNA–RNA interactions. Mutations in the splice sites, exonic and intronic sequences lead to aberrant exon usage. Mutations can cause exon skipping, a change in the degree of exon usage or activate sequences on the pre‐mRNA to become a new exon. Synonymous mutations in exons can cause their aberrant usage, which can be a disease mechanism. A pathological change in the activity of splicing regulatory proteins results in numerous, individually small changes of alternative exon usage. Aberrant exon usage can be targeted by rationale therapies, several oligonucleotide‐based treatments are tested in clinical trials and small molecules were identified that change splice site selection by high‐throughput screens.

SpliceProt 2.0: A Sequence Repository of Human, Mouse, and Rat Proteoforms

“…AS is a molecular mechanism that strongly impacts the proteome and should not be overlooked when building optimized sequence repositories [18,20,22]. Errors and aberrations in AS may result in the development of numerous human diseases, including cancer, Alzheimer's disease, Duchenne muscular dystrophy, and lateral amyotrophic sclerosis [13][14][15]23,24]. Faulty AS can result in the production of a truncated protein through the introduction of a premature termination code (PTC) in transcripts [25,26].…”