title: Ablation of the X-linked retinitis pigmentosa 2 (Rp2) gene in mice results in opsin mislocalization and photoreceptor degeneration.
abstract: OBJECTIVE
  Mutations in the RP2 gene are associated with 10% to 15% of X-linked retinitis pigmentosa (XLRP), a debilitating disorder characterized by the degeneration of retinal rod and cone photoreceptors. The molecular mechanism of pathogenesis of photoreceptor degeneration in XLRP-RP2 has not been elucidated, and no treatment is currently available. This study was undertaken to investigate the pathogenesis of RP2-associated retinal degeneration.
  
  
  METHODS
  We introduced loxP sites that flank exon 2, a mutational hotspot in XLRP-RP2, in the mouse Rp2 gene. We then produced Rp2-null allele using transgenic mice that expressed Cre-recombinase under control of the ubiquitous CAG promoter. Electroretinography (ERG), histology, light microscopy, transmission electron microscopy, and immunofluorescence microscopy were performed to ascertain the effect of ablation of Rp2 on photoreceptor development, function, and protein trafficking.
  
  
  RESULTS
  Although no gross abnormalities were detected in the Rp2(null) mice, photopic (cone) and scotopic (rod) function as measured by ERG showed a gradual decline starting as early as 1 month of age. We also detected slow progressive degeneration of the photoreceptor membrane discs in the mutant retina. These defects were associated with mislocalization of cone opsins to the nuclear and synaptic layers and reduced rhodopsin content in the outer segment of mutant retina prior to the onset of photoreceptor degeneration.
  
  
  CONCLUSIONS
  Our studies suggest that RP2 contributes to the maintenance of photoreceptor function and that cone opsin mislocalization represents an early step in XLRP caused by RP2 mutations. The Rp2(null) mice should serve as a useful preclinical model for testing gene- and cell-based therapies.
authors.affiliation: Department of Ophthalmology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Linjing
authors.initials: L
authors.lastname: Li
authors.forename: Naheed
authors.initials: N
authors.lastname: Khan
authors.forename: Toby
authors.initials: T
authors.lastname: Hurd
authors.forename: Amiya Kumar
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Christiana
authors.initials: C
authors.lastname: Cheng
authors.forename: Robert
authors.initials: R
authors.lastname: Molday
authors.forename: John R
authors.initials: JR
authors.lastname: Heckenlively
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
authors.forename: Hemant
authors.initials: H
authors.lastname: Khanna
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics; D019204:GTP-Binding Proteins; D050172:Genes, X-Linked / Q000235:genetics*; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D055355:Opsins / Q000378:metabolism*; D010786:Photoreceptor Cells / Q000473:pathology*; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology
chemical_list: D005136:Eye Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D055355:Opsins; C072178:RP2 protein, human; D019204:GTP-Binding Proteins
keywords: Rp2; photoreceptor; retina