The Mechanism for Mutations in HPRP3 Leading to Retinitis Pigmentosa
Jim Hu, Ph.D.
Departments of Pediatrics, and Laboratory Medicine and Pathology
Hospital for Sick Children Research Institute
The Hospital for Sick Children, Toronto, Ontario
Retinitis Pigmentosa (RP) refers to a group of hereditary retinal dystrophies characterized by a progressive loss of vision. It currently affects more than 1.5 million individuals worldwide. Mutations in at least 36 genes are linked to RP although the mechanism underlying the disease process is not clear.
Recently, mutations in three splicing factor genes were reported to cause RP. Analyses of mutations in this unique class of genes should gain new insight into the mechanism of the RP pathogenesis. One of these genes, HPRP3, which encodes a human splicing factor, was first cloned and extensively studied in my laboratory.
The objective of this proposal is to investigate the mechanism by which mutations in this gene lead to RP. We propose two complementary hypotheses to explain the mechanism of this class of mutations causing RP. Our first hypothesis is that photoreceptor cells may be more susceptible to mutations affecting gene expression because these cells are metabolically more active. Alternatively, we propose that these mutations may affect their interactions with retina-specific factors that regulate RNA splicing. We plan to use molecular approaches to examine whether these mutations affect key interactions in the splicing machinery. We will also take a new approach to study the mutations in mice and to design novel gene therapy strategies for RP.