title: Cloning of the canine ABCA4 gene and evaluation in canine cone-rod dystrophies and progressive retinal atrophies.
abstract: OBJECTIVE
  To characterize a novel early onset canine retinal disease, and evaluate the ATP-binding cassette transporter gene ABCA4 as a potential candidate gene in this and other canine retinal degenerations.
  
  
  METHODS
  Retinal disease was characterized ophthalmoscopically and electroretinographically in two pit bull terrier dogs and their purpose-bred descendants. All 50 exons of the canine ABCA4 gene were amplified, cloned and sequenced from retinal mRNA of a normal, a carrier and an affected animal, and polymorphisms identified. The latter were used to search for association between ABCA4 and retinal disease both within the study pedigrees and in additional canine breeds segregating retinal degenerations.
  
  
  RESULTS
  The disease derived from either founder is distinguished by early, severe, and rapidly progressive loss of cone function accompanied by progressive rod loss that is only relatively slower. Cloning and comparative sequencing of ABCA4 identified six point mutations, none of which were obviously pathogenic. Crossbreeding studies revealed that the diseases in the two founders, although similar, are nonallelic. Pedigree analysis of segregating polymorphisms revealed dissociation between ABCA4 and both retinal phenotypes.
  
  
  CONCLUSIONS
  The early, severe cone dysfunction in these diseases distinguish them from other forms of canine Progressive Retinal Atrophy. The development of a research population segregating these diseases presents two large animal models for the heterogenous human diseases termed cone-rod dystrophies. Analysis of the canine ABCA4 homolog gene documented its sequence and identified a set of point mutations that were used to exclude this gene as causal to these canine cone-rod dystrophies.
authors.affiliation: James A. Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Kijas
authors.forename: Barbara
authors.initials: B
authors.lastname: Zangerl
authors.forename: Brian
authors.initials: B
authors.lastname: Miller
authors.forename: Jacque
authors.initials: J
authors.lastname: Nelson
authors.forename: Ewen F
authors.initials: EF
authors.lastname: Kirkness
authors.forename: Gustavo D
authors.initials: GD
authors.lastname: Aguirre
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Acland
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001284:Atrophy; D001483:Base Sequence; D003001:Cloning, Molecular; D018450:Disease Progression; D004283:Dog Diseases / Q000235:genetics* / Q000503:physiopathology; D004285:Dogs; D004596:Electroretinography / Q000662:veterinary; D005260:Female; D008297:Male; D008969:Molecular Sequence Data; D009887:Ophthalmoscopy / Q000662:veterinary; D010375:Pedigree; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology*; D017354:Point Mutation; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D021101:Radiation Hybrid Mapping / Q000662:veterinary; D012160:Retina / Q000473:pathology*; D012162:Retinal Degeneration / Q000235:genetics / Q000503:physiopathology / Q000662:veterinary*
chemical_list: D018528:ATP-Binding Cassette Transporters; D012333:RNA, Messenger