title: Retinal degeneration 12 (rd12): a new, spontaneously arising mouse model for human Leber congenital amaurosis (LCA).
abstract: OBJECTIVE
  To report the phenotype and characterization of a new, naturally occurring mouse model of hereditary retinal degeneration (rd12).
  
  
  METHODS
  The retinal phenotype of rd12 mice were studied using serial indirect ophthalmoscopy, fundus photography, electroretinography (ERG), genetic analysis including linkage studies and gene identification, immunohistochemistry, and biochemical analysis.
  
  
  RESULTS
  Mice homozygous for the rd12 mutation showed small punctate white spots on fundus examination at 5 months of age. The retina in the rd12 homozygote had a normal appearance at the light microscopic level until 6 weeks of age when occasional voids appeared in the outer segments (OS) of the photoreceptor (PR) cells. The outer nuclear layer (ONL) appeared normal until 3 months of age though more obvious voids were detected in the OS. By 7 months of age, 6 to 8 layers of ONL remained in the mutant retina, and the OS were obviously shorter. The first sign of retinal degeneration was detected at the electron microscopic level around 3 weeks of age when occasional small lipid-like droplets were detected in the retinal pigment epithelium (RPE). By 3 months of age, much larger, lipid-like droplets accumulated in RPE cells accompanied by some OS degeneration. While the histology indicated a relatively slow retinal degeneration in the rd12 homozygous mutant mice, the rod ERG response was profoundly diminished even at 3 weeks of age. Genetic analysis showed that rd12 was an autosomal recessive mutation and mapped to mouse chromosome 3 closely linked to D3Mit19, a location known to be near the mouse Rpe65 gene. Sequence analysis showed that the mouse retinal degeneration is caused by a nonsense mutation in exon 3 of the Rpe65 gene, and the gene symbol for the rd12 mutation has been updated to Rpe65rd12 to reflect this. No RPE65 expression, 11-cis retinal, or rhodopsin could be detected in retinas from rd12 homozygotes, while retinyl esters were found to accumulate in the retinal pigment epithelium (RPE).
  
  
  CONCLUSIONS
  Mutations in the retinal pigment epithelium gene encoding RPE65 cause an early onset autosomal recessive form of human retinitis pigmentosa, known as Leber congenital amaurosis (LCA), which results in blindness or severely impaired vision in children. A naturally arising mouse Rpe65 mutation provides a good model for studying the pathology of human RPE65 mutations and the effects of retinyl ester accumulation.
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, USA.
authors.forename: Ji-Jing
authors.initials: JJ
authors.lastname: Pang
authors.forename: Bo
authors.initials: B
authors.lastname: Chang
authors.forename: Norman L
authors.initials: NL
authors.lastname: Hawes
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Hurd
authors.forename: Muriel T
authors.initials: MT
authors.lastname: Davisson
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Syed M
authors.initials: SM
authors.lastname: Noorwez
authors.forename: Ritu
authors.initials: R
authors.lastname: Malhotra
authors.forename: J Hugh
authors.initials: JH
authors.lastname: McDowell
authors.forename: Shalesh
authors.initials: S
authors.lastname: Kaushal
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.forename: Steven
authors.initials: S
authors.lastname: Nusinowitz
authors.forename: Debra A
authors.initials: DA
authors.lastname: Thompson
authors.forename: John R
authors.initials: JR
authors.lastname: Heckenlively
mesh_terms: D000818:Animals; D001766:Blindness / Q000151:congenital* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins; D018389:Codon, Nonsense; D004195:Disease Models, Animal; D004596:Electroretinography; D005091:Exons / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009887:Ophthalmoscopy; D010641:Phenotype; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology; D010857:Pigment Epithelium of Eye / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012172:Retinaldehyde / Q000378:metabolism; D012243:Rhodopsin / Q000378:metabolism; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
chemical_list: D002352:Carrier Proteins; D018389:Codon, Nonsense; D005136:Eye Proteins; D012172:Retinaldehyde; D012243:Rhodopsin; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase