title: Three gene-targeted mouse models of RNA splicing factor RP show late-onset RPE and retinal degeneration.
abstract: OBJECTIVE
  Mutations in genes that produce proteins involved in mRNA splicing, including pre-mRNA processing factors 3, 8, and 31 (PRPF3, 8, and 31), RP9, and SNRNP200 are common causes of the late-onset inherited blinding disorder retinitis pigmentosa (RP). It is not known how mutations in these ubiquitously expressed genes lead to retina-specific disease. To investigate the pathogenesis of the RNA splicing factor forms of RP, the authors generated and characterized the retinal phenotypes of Prpf3-T494M, Prpf8-H2309P knockin mice. The retinal ultrastructure of Prpf31-knockout mice was also investigated.
  
  
  METHODS
  The knockin mice have single codon alterations in their endogenous Prpf3 and Prpf8 genes that mimic the most common disease causing mutations in human PRPF3 and PRPF8. The Prpf31-knockout mice mimic the null alleles that result from the majority of mutations identified in PRPF31 patients. The retinal phenotypes of the gene targeted mice were evaluated by electroretinography (ERG), light, and electron microscopy.
  
  
  RESULTS
  The RPE cells of heterozygous Prpf3(+/T494M) and Prpf8(+/H2309P) knockin mice exhibited loss of the basal infoldings and vacuolization, with accumulation of amorphous deposits between the RPE and Bruch[b]'s membrane at age two years. These changes were more severe in the homozygous mice, and were associated with decreased rod function in the Prpf3-T494M mice. Similar degenerative changes in the RPE were detected in Prpf31(±) mice at one year of age.
  
  
  CONCLUSIONS
  The finding of similar degenerative changes in RPE cells of all three mouse models suggests that the RPE may be the primary cell type affected in the RNA splicing factor forms of RP. The relatively late-onset phenotype observed in these mice is consistent with the typical adult onset of disease in patients with RP.
authors.affiliation: University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Graziotto
authors.forename: Michael H
authors.initials: MH
authors.lastname: Farkas
authors.forename: Kinga
authors.initials: K
authors.lastname: Bujakowska
authors.forename: Bertrand M
authors.initials: BM
authors.lastname: Deramaudt
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Emeline F
authors.initials: EF
authors.lastname: Nandrot
authors.forename: Chris F
authors.initials: CF
authors.lastname: Inglehearn
authors.forename: Shomi S
authors.initials: SS
authors.lastname: Bhattacharya
authors.forename: Eric A
authors.initials: EA
authors.lastname: Pierce
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D004195:Disease Models, Animal; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D055879:Gene Knock-In Techniques; D005838:Genotype; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012326:RNA Splicing / Q000235:genetics*; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000235:genetics*; D055213:Retinal Pigment Epithelium / Q000648:ultrastructure*; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology; D017414:Ribonucleoprotein, U4-U6 Small Nuclear / Q000235:genetics*; D014162:Transfection
chemical_list: D005136:Eye Proteins; C555603:PRPF31 protein, mouse; C433464:Prp8 protein, mouse; C532027:Prpf3 protein, mouse; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D017414:Ribonucleoprotein, U4-U6 Small Nuclear
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