title: Mutation discovered in a feline model of human congenital retinal blinding disease.
abstract: OBJECTIVE
  To elucidate the gene defect in a pedigree of cats segregating for autosomal dominant rod-cone dysplasia (Rdy), a retinopathy characterized extensively from a clinical perspective. Disease expression in Rdy cats is comparable to that in young patients with congenital blindness (Leber congenital amaurosis [LCA] or retinitis pigmentosa [RP]).
  
  
  METHODS
  A pedigree segregating for Rdy was generated and phenotyped by clinical ophthalmic examination methods including ophthalmoscopy and full-field flash electroretinography. Short tandem repeat loci tightly linked to candidate genes for autosomal dominant retinitis pigmentosa in humans were genotyped in the pedigree.
  
  
  RESULTS
  Significant linkage was established to the candidate gene CRX (LOD = 5.56, = 0) on cat chromosome E2. A single base pair deletion was identified in exon 4 (n.546delC) in affected individuals but not in unaffected littermates. This mutation generates a frame shift in the transcript, introducing a premature stop codon truncating the putative CRX peptide, which would eliminate the critical transcriptional activation region. Clinical observations corroborate previously reported clinical reports about Rdy. Results show that the cone photoreceptor system was more severely affected than the rods in the early disease process.
  
  
  CONCLUSIONS
  A putative mutation causative of the Rdy phenotype has been described as a single base pair deletion in exon 4 of the CRX gene, thus identifying the first animal model for CRX-linked disease that closely resembles the human disease. As such, it will provide valuable insights into the mechanisms underlying these diseases and their variable presentation, as well as providing a suitable model for testing therapies for these diseases.
authors.affiliation: Laboratory of Genomic Diversity, National Cancer Institute-Frederick, Frederick, Maryland 21702, USA. raymondm@mail.nih.gov
authors.forename: Marilyn
authors.initials: M
authors.lastname: Menotti-Raymond
authors.forename: Koren Holland
authors.initials: KH
authors.lastname: Deckman
authors.forename: Victor
authors.initials: V
authors.lastname: David
authors.forename: Jaimie
authors.initials: J
authors.lastname: Myrkalo
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: O'Brien
authors.forename: Kristina
authors.initials: K
authors.lastname: Narfström
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002371:Cat Diseases / Q000235:genetics* / Q000473:pathology; D002415:Cats; D002874:Chromosome Mapping; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis / Q000662:veterinary; D003623:Dark Adaptation; D004195:Disease Models, Animal; D004596:Electroretinography / Q000662:veterinary; D005091:Exons / Q000235:genetics; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology*; D015792:Retinal Dysplasia / Q000235:genetics / Q000473:pathology / Q000662:veterinary*; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D018398:Homeodomain Proteins; D015534:Trans-Activators; C109288:cone rod homeobox protein