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The Journal of Neuroscience, January 19, 2005, 25(3):748-757; doi:10.1523/JNEUROSCI.2399-04.2005

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Neurobiology of Disease
Mutations in PRPF31 Inhibit Pre-mRNA Splicing of Rhodopsin Gene and Cause Apoptosis of Retinal Cells

Liya Yuan,¹ Mariko Kawada,¹ Necat Havlioglu,² Hao Tang,¹ and Jane Y. Wu¹

¹Departments of Pediatrics, Cell and Developmental Biology, and Pharmacology, John F. Kennedy Center for Research on Human Development, and Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee 37232, and ²Department of Pathology, St. Louis University, St. Louis, Missouri 63110

Mutations in human PRPF31 gene have been identified in patients with autosomal dominant retinitis pigmentosa (adRP). To begin to understand mechanisms by which defects in this general splicing factor cause retinal degeneration, we examined the relationship between PRPF31 and pre-mRNA splicing of photoreceptor-specific genes. We used a specific anti-PRPF31 antibody to immunoprecipitate splicing complexes from retinal cells and identified the transcript of rhodopsin gene (RHO) among RNA species associated with PRPF31-containing complexes. Mutant PRPF31 proteins significantly inhibited pre-mRNA splicing of intron 3 in RHO gene. In primary retinal cell cultures, expression of the mutant PRPF31 proteins reduced rhodopsin expression and caused apoptosis of rhodopsin-positive retinal cells. This primary retinal culture assay provides an in vitro model to study photoreceptor cell death caused by PRPF31 mutations. Our results demonstrate that mutations in PRPF31 gene affect RHO pre-mRNA splicing and reveal a link between PRPF31 and RHO, two major adRP genes.

Key words: autosomal dominant retinitis pigmentosa (adRP); PRPF31; pre-mRNA splicing; retinal cells; apoptosis; rhodopsin

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Received Jan 23, 2004; revised November 21, 2004; accepted November 22, 2004.

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