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      Identification of photoreceptor genes affected by PRPF31 mutations associated with autosomal dominant retinitis pigmentosa.

      Neurobiology of Disease
      Alternative Splicing, genetics, Animals, Animals, Newborn, Carrier Proteins, biosynthesis, Cell Line, Cells, Cultured, Chickens, Chromosome Disorders, metabolism, physiopathology, Eye Proteins, Gene Expression Regulation, Developmental, Genes, Dominant, Genetic Predisposition to Disease, Humans, Intermediate Filament Proteins, Membrane Glycoproteins, Mice, Mice, Inbred Strains, Microfilament Proteins, Mutation, Nerve Tissue Proteins, Oligonucleotide Array Sequence Analysis, Peripherins, Photoreceptor Cells, RNA Precursors, RNA Splicing, Retinitis Pigmentosa

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          Abstract

          Several ubiquitously expressed genes encoding pre-mRNA splicing factors have been associated with autosomal dominant retinitis pigmentosa (adRP), including PRPF31, PRPF3 and PRPF8. Molecular mechanisms by which defects in pre-mRNA splicing factors cause photoreceptor degeneration are not clear. To investigate the role of pre-mRNA splicing in photoreceptor gene expression and function, we have begun to search for photoreceptor genes whose pre-mRNA splicing is affected by mutations in PRPF31. Using an immunoprecipitation-coupled-microarray method, we identified a number of transcripts associated with PRPF31-containing complexes, including peripherin/RDS, FSCN2 and other photoreceptor-expressed genes. We constructed minigenes to study the effects of PRPF31 mutations on the pre-mRNA splicing of these photoreceptor specific genes. Our experiments demonstrated that mutant PRPF31 significantly inhibited pre-mRNA splicing of RDS and FSCN2. These observations suggest a functional link between ubiquitously expressed and retina-specifically expressed adRP genes. Our results indicate that PRPF31 mutations lead to defective pre-mRNA splicing of photoreceptor-specific genes and that the ubiquitously expressed adRP gene, PRPF31, is critical for pre-mRNA splicing of a subset of photoreceptor genes. Our results provide an explanation for the photoreceptor-specific phenotype of PRPF31 mutations.

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