Pre-mRNA splicing is a critical step in mammalian gene expression. Defects in pre-mRNA splicing cause a large number of human diseases. Recent studies have identified mutations in three genes encoding general splicing factors, HPRP3, PRPC8, or PRPF31, as genetic defects causing autosomal dominant forms of retinitis pigrnentosa (adRP). The molecular mechanisms underlying such genetic defects remain to be elucidated. In our preliminary study, we have established primary retinal neuron cultures and found that expression of mutant PRPF31 proteins reduce the survival of retinal neurons. We propose to apply our expertise in studying pre-mRNA splicing regulation, programmed cell death and neurodegeneration to investigating the pathogenetic mechanisms underlying RP-causing mutations in human PRPF31 gene. We plan to use cell culture systems to examine the activities of wild-type and RP-mutant forms of PRPF31. We will search for target genes for PRPF31 using microarray and biochemical approaches. We will examine functional mechanisms by which PRPF31 mutations lead to retinal degeneration. This study will reveal potential new players in the pathogenesis of retinal degeneration. It is highly likely that the proposed study will contribute to understanding the basic mechanism of pre-mRNA splicing regulation and provide insights into the pathogenesis of adRP. This study will not only help in our understanding of adRP but also likely provide new information on other neurodegenerative disorders. Furthermore, correcting the underlying splicing defects will make inroads toward new treatment for these diseases.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Special Emphasis Panel (ZRG1-VISC (01))
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Dudley, Peter A
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Vanderbilt University Medical Center
Schools of Medicine
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