title: CrxRdy Cat: A Large Animal Model for CRX-Associated Leber Congenital Amaurosis.
abstract: OBJECTIVE
  Mutations in the retinal transcription factor cone-rod homeobox (CRX) gene result in severe dominant retinopathies. A large animal model, the Rdy cat, carrying a spontaneous frameshift mutation in Crx, was reported previously. The present study aimed to further understand pathogenesis in this model by thoroughly characterizing the Rdy retina.
  
  
  METHODS
  Structural and functional changes were found in a comparison between the retinas of CrxRdy/+ kittens and those of wild-type littermates and were determined at various ages by fundus examination, electroretinography (ERG), optical coherence tomography, and histologic analyses. RNA and protein expression changes of Crx and key target genes were analyzed using quantitative reverse-transcribed PCR, Western blot analysis, and immunohistochemistry. Transcription activity of the mutant Crx was measured by a dual-luciferase transactivation assay.
  
  
  RESULTS
  CrxRdy/+ kittens had no recordable cone ERGs. Rod responses were delayed in development and markedly reduced at young ages and lost by 20 weeks. Photoreceptor outer segment development was incomplete and was followed by progressive outer retinal thinning starting in the cone-rich area centralis. Expression of cone and rod Crx target genes was significantly down-regulated. The mutant Crx allele was overexpressed, leading to high levels of the mutant protein lacking transactivation activity.
  
  
  CONCLUSIONS
  The CrxRdy mutation exerts a dominant negative effect on wild-type Crx by overexpressing mutant protein. These findings, consistent with those of studies in a mouse model, support a conserved pathogenic mechanism for CRX frameshift mutations. The similarities between the feline eye and the human eye with the presence of a central region of high cone density makes the CrxRdy/+ cat a valuable model for preclinical testing of therapies for dominant CRX diseases.
authors.affiliation: Small Animal Clinical Sciences Michigan State University, East Lansing, Michigan, United States.
authors.forename: Laurence M
authors.initials: LM
authors.lastname: Occelli
authors.affiliation: Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, United States.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Tran
authors.affiliation: Department of Veterinary Medicine and Surgery, University of Missouri-Columbia, Columbia, Missouri, United States.
authors.forename: Kristina
authors.initials: K
authors.lastname: Narfström
authors.affiliation: Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, United States.
authors.forename: Shiming
authors.initials: S
authors.lastname: Chen
authors.affiliation: Small Animal Clinical Sciences Michigan State University, East Lansing, Michigan, United States.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Petersen-Jones
mesh_terms: D000818:Animals; D002415:Cats; D003623:Dark Adaptation / Q000502:physiology; D004195:Disease Models, Animal; D016368:Frameshift Mutation / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D057130:Leber Congenital Amaurosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D012160:Retina / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D012684:Sensory Thresholds / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D018398:Homeodomain Proteins; D015534:Trans-Activators; C109288:cone rod homeobox protein