2020–2021 BCSC Basic and Clinical Science Course™
2 Fundamentals and Principles of Ophthalmology
Part III: Genetics
Chapter 5: Molecular Genetics
Gene Transcription and Translation: The Central Dogma of Genetics
Alternative Splicing and Isoforms
Alternative splicing is the creation of multiple pre-mRNA sequences from the same gene by the action of different promoters. These promoters cause certain exons to be skipped during transcription of the gene. The protein products of alternative splicing are often called isoforms. The promoters are usually tissue specific, so different tissues express different isoforms. The gene for dystrophin is an example of alternative splicing: full-length dystrophin is the major isoform expressed in muscle; shorter isoforms predominate in the retina, peripheral nerve, and central nervous system.
Another example of alternative splicing’s relevance underlies the basis of the cornea’s avascularity. Vascular endothelial growth factor (VEGF) receptor 1 is a key blood vessel receptor that binds and transduces a signal from the primary mediator of angiogenesis, VEGF. In the cornea, high levels of an alternatively spliced isoform, soluble VEGF receptor 1 (sVEGFR-1), are expressed. As this isoform is soluble, it is present in the extracellular matrix and serves as an endogenous VEGF trap or decoy receptor. Without it, there are increased levels of free VEGF, and the cornea becomes vulnerable to vascular invasion.
Ambati BK, Nozaki M, Singh N, et al. Corneal avascularity is due to soluble VEGF receptor-1. Nature. 2006;443(7114):993–997.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.