title: Characterization of a canine model of autosomal recessive retinitis pigmentosa due to a PDE6A mutation.
abstract: OBJECTIVE
  To characterize a canine model of autosomal recessive RP due to a PDE6A gene mutation.
  
  
  METHODS
  Affected and breed- and age-matched control puppies were studied by electroretinography (ERG), light and electron microscopy, immunohistochemistry, and assay for retinal PDE6 levels and enzymatic activity.
  
  
  RESULTS
  The mutant puppies failed to develop normal rod-mediated ERG responses and had reduced light-adapted a-wave amplitudes from an early age. The residual ERG waveforms originated primarily from cone-driven responses. Development of photoreceptor outer segments stopped, and rod cells were lost by apoptosis. Immunohistochemistry demonstrated a marked reduction in rod opsin immunostaining outer segments and relative preservation of cones early in the disease process. With exception of rod bipolar cells, which appeared to be reduced in number relatively early in the disease process, other inner retinal cells were preserved in the early stages of the disease, although there was marked and early activation of Müller glia. Western blot analysis showed that the PDE6A mutation not only resulted in a lack of PDE6A protein but the affected retinas also lacked the other PDE6 subunits, suggesting expression of PDE6A is essential for normal expression of PDE6B and PDE6G. Affected retinas lacked PDE6 enzymatic activity.
  
  
  CONCLUSIONS
  This represents the first characterization of a PDE6A model of autosomal recessive retinitis pigmentosa, and the PDE6A mutant dog shows promise as a large animal model for investigation of therapies to rescue mutant rod photoreceptors and to preserve cone photoreceptors in the face of a rapid loss of rod cells.
authors.affiliation: Department of Small Animal Clinical Studies, Michigan State University, East Lansing, Michigan 48824, USA.
authors.forename: Nalinee
authors.initials: N
authors.lastname: Tuntivanich
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Pittler
authors.forename: Andy J
authors.initials: AJ
authors.lastname: Fischer
authors.forename: Ghezal
authors.initials: G
authors.lastname: Omar
authors.forename: Matti
authors.initials: M
authors.lastname: Kiupel
authors.forename: Arthur
authors.initials: A
authors.lastname: Weber
authors.forename: Suxia
authors.initials: S
authors.lastname: Yao
authors.forename: Juan Pedro
authors.initials: JP
authors.lastname: Steibel
authors.forename: Naheed Wali
authors.initials: NW
authors.lastname: Khan
authors.forename: Simon M
authors.initials: SM
authors.lastname: Petersen-Jones
mesh_terms: D000818:Animals; D015153:Blotting, Western / Q000662:veterinary; D001947:Breeding; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics*; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000235:genetics* / Q000503:physiopathology; D004285:Dogs; D004596:Electroretinography / Q000662:veterinary; D005260:Female; D005808:Genes, Recessive; D007150:Immunohistochemistry / Q000662:veterinary; D020287:In Situ Nick-End Labeling; D008297:Male; D017354:Point Mutation; D012160:Retina / Q000503:physiopathology; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000503:physiopathology / Q000662:veterinary*
chemical_list: D054707:Cyclic Nucleotide Phosphodiesterases, Type 6
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