title: IQCB1 and PDE6B mutations cause similar early onset retinal degenerations in two closely related terrier dog breeds.
abstract: OBJECTIVE
  To identify the causative mutations in two early-onset canine retinal degenerations, crd1 and crd2, segregating in the American Staffordshire terrier and the Pit Bull Terrier breeds, respectively.
  
  
  METHODS
  Retinal morphology of crd1- and crd2-affected dogs was evaluated by light microscopy. DNA was extracted from affected and related unaffected controls. Association analysis was undertaken using the Illumina Canine SNP array and PLINK (crd1 study), or the Affymetrix Version 2 Canine array, the "MAGIC" genotype algorithm, and Fisher's Exact test for association (crd2 study). Positional candidate genes were evaluated for each disease.
  
  
  RESULTS
  Structural photoreceptor abnormalities were observed in crd1-affected dogs as young as 11-weeks old. Rod and cone inner segment (IS) and outer segments (OS) were abnormal in size, shape, and number. In crd2-affected dogs, rod and cone IS and OS were abnormal as early as 3 weeks of age, progressing with age to severe loss of the OS, and thinning of the outer nuclear layer (ONL) by 12 weeks of age. Genome-wide association study (GWAS) identified association at the telomeric end of CFA3 in crd1-affected dogs and on CFA33 in crd2-affected dogs. Candidate gene evaluation identified a three bases deletion in exon 21 of PDE6B in crd1-affected dogs, and a cytosine insertion in exon 10 of IQCB1 in crd2-affected dogs.
  
  
  CONCLUSIONS
  Identification of the mutations responsible for these two early-onset retinal degenerations provides new large animal models for comparative disease studies and evaluation of potential therapeutic approaches for the homologous human diseases.
authors.affiliation: Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, New York.
authors.forename: Orly
authors.initials: O
authors.lastname: Goldstein
authors.forename: Jason G
authors.initials: JG
authors.lastname: Mezey
authors.forename: Peter A
authors.initials: PA
authors.lastname: Schweitzer
authors.forename: Adam R
authors.initials: AR
authors.lastname: Boyko
authors.forename: Chuan
authors.initials: C
authors.lastname: Gao
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Bustamante
authors.forename: Julie Ann
authors.initials: JA
authors.lastname: Jordan
authors.forename: Gustavo D
authors.initials: GD
authors.lastname: Aguirre
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Acland
mesh_terms: D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D008297:Male; D009154:Mutation; D010375:Pedigree; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism* / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D002148:Calmodulin-Binding Proteins; C498171:IQCB1 protein, human; D004247:DNA; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517431:PDE6B protein, human
keywords: GWAS; mutation; retina
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