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. Such missplicing can be caused by mutations in DNA (deoxyribonucleic acid), mutations in splicing factors and changes in the concentration of splicing factors. The effect of these mutations can be predicted using bioinformatic tools, but any prediction needs to be validated experimentally. Advances in understanding the molecular mechanisms regulating splice site selection resulted in the development of treatment options using RNA (ribonucleic acid) oligonucleotides as well as small molecules that inhibit or alter alternative splicing. Oligonucleotides for treatment of spinal muscular atrophy and Duchenne muscular dystrophy have advanced into clinical trials and serve as a paradigm for the treatment of other diseases caused by missplicing.
Key Concepts
- Mechanism of alternative splice site selection.
- Changes in alternative splicing caused by mutations that result in disease.
- Mutations leading to a change in alternative splicing.
- Analysis of mutations that change splice site selection.
- Splicing-changing oligonucleotides to treat diseases.
- Small molecules as splicing inhibitors or modulators to treat diseases.
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Further Reading
- Chabot B and Shkreta L (2016) Defective control of pre-messenger RNA splicing in human disease. The Journal of Cell Biology 212 (1): 13–27. PMID: 26728853.
- Daguenet E, Dujardin G and Valcarcel J (2015) The pathogenicity of splicing defects: mechanistic insights into pre-mRNA processing inform novel therapeutic approaches. EMBO Reports 16 (12): 1640–1655. PMID: 26566663.
- Singh RK and Cooper TA (2012) Pre-mRNA splicing in disease and therapeutics. Trends in Molecular Medicine 18 (8): 472–482. PMID: 22819011.
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Stamm S, Smith C and Lührmann R (2012) Alternative Pre-mRNA Splicing: Theory and Applications. Weinheim: Wiley-Blackwell.
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