title: Identification of photoreceptor genes affected by PRPF31 mutations associated with autosomal dominant retinitis pigmentosa.
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.
authors.affiliation: Department of Pediatrics, John F. Kennedy Center for Research on Human Development, Vanderbilt University Medical Center, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mordes
authors.forename: Liya
authors.initials: L
authors.lastname: Yuan
authors.forename: Lili
authors.initials: L
authors.lastname: Xu
authors.forename: Mariko
authors.initials: M
authors.lastname: Kawada
authors.forename: Robert S
authors.initials: RS
authors.lastname: Molday
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Wu
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D002645:Chickens; D025063:Chromosome Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005136:Eye Proteins / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005799:Genes, Dominant / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008840:Microfilament Proteins / Q000096:biosynthesis / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D064531:Peripherins; D010786:Photoreceptor Cells / Q000378:metabolism* / Q000503:physiopathology; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism*; D012326:RNA Splicing / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D002352:Carrier Proteins; D005136:Eye Proteins; D007381:Intermediate Filament Proteins; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; C454222:PRPF31 protein, human; C578994:PRPH protein, human; C578997:PRPH2 protein, human; D064531:Peripherins; C578996:Prph2 protein, mouse; D012322:RNA Precursors; C020324:fascin