Jonathan P. Staley, PhD

The University of Chicago - Visionary

Project title: "The consequences of splicing factor mutations in autosomal dominant retinitis pigmentosa"

 

One third of all cases of a common form of blindness, retinitis pigmentosa, are inherited. These cases result from variations in one of over forty genes. Most of these genes encode proteins that function specifically in the retina of the eye. However, a significant fraction of these genes encode products that function throughout the body. These products help direct the synthesis of proteins, which is dictated by the information encoded in genes. In humans, genes are dominated by and interrupted by introns, which do not encode information that dictates the synthesis of a protein. Consequently, before a message conveys the information in a gene to the factory that synthesizes the corresponding proteins, the introns must be excised by a molecular machine termed the spliceosome, a machine that must be activated each time it excises an intron. Mutations in at least five components belonging to a single compartment of this machinery confer retinitis pigmentosa. It remains a mystery as to why variations in these ubiquitous genes confer specific defects in the retina. The long-term goal of this project is to solve this mystery.
The short-term goal is to define the immediate consequences of variations in these genes linked to retinitis pigmentosa. Previous work suggested that these genes prevented efficient assembly of the spliceosomal machinery, an efficiency that may be important in the retina where many proteins suffer damage from light and require rapid replacement. However, our recent work has shown for at least one of these genes that a variation linked to retinitis pigmentosa allows assembly of the spliceosome but inhibits activation of the spliceosome. The specific goal of this project is to test whether mutations in all of the splicing genes linked to retinitis pigmentosa similarly impede activation of the spliceosomal machinery. This project will fundamentally impact our understanding of the etiology of retinitis pigmentosa linked to splicing genes. Additionally, this project will lay the foundation for improved diagnosis, prevention and treatment of retinitis pigmentosa.