title: Identification of genetic variation and haplotype structure of the canine ABCA4 gene for retinal disease association studies.
abstract: Over 200 mutations in the retina specific member of the ATP-binding cassette transporter superfamily (ABCA4) have been associated with a diverse group of human retinal diseases. The disease mechanisms, and genotype-phenotype associations, nonetheless, remain elusive in many cases. As orthologous genes are commonly mutated in canine models of human blinding disorders, canine ABCA4 appears to be an ideal candidate gene to identify and study sequence changes in dogs affected by various forms of inherited retinal degeneration. However, the size of the gene and lack of haplotype assignment significantly limit targeted association and/or linkage approaches. This study assessed the naturally observed sequence diversity of ABCA4 in the dog, identifying 80% of novel variations. While none of the observed polymorphisms have been associated with blinding disorders to date, breed and potentially disease specific haplotypes have been identified. Moreover, a tag SNP map of 17 (15) markers has been established that accurately predicts common ABCA4 haplotypes (frequency > 5%) explaining >85% (>80%) of the observed genetic diversity and will considerably advance future studies. Our sequence analysis of the complete canine ABCA4 coding region will clearly provide a baseline and tools for future association studies and comparative genomics to further delineate the role of ABCA4 in canine blinding disorders.
authors.affiliation: Section of Ophthalmology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. bzangerl@vet.upenn.edu
authors.forename: B
authors.initials: B
authors.lastname: Zangerl
authors.forename: S J
authors.initials: SJ
authors.lastname: Lindauer
authors.forename: G M
authors.initials: GM
authors.lastname: Acland
authors.forename: G D
authors.initials: GD
authors.lastname: Aguirre
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D019943:Amino Acid Substitution; D000818:Animals; D004283:Dog Diseases / Q000235:genetics; D004285:Dogs / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D023421:Models, Animal; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012162:Retinal Degeneration / Q000235:genetics / Q000662:veterinary; D012164:Retinal Diseases / Q000235:genetics*; D013045:Species Specificity
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters