Exclusion of eleven candidate genes for ocular melanosis in cairn terriers

Abstract

BackgroundOcular melanosis of Cairn terrier dogs is an inherited defect characterized by progressive pigmentation of both eyes which can result in glaucoma and blindness. Pedigree analysis suggests the trait has an autosomal dominant mode of inheritance. We selected 11 potential candidate genes and used an exclusion analysis approach to investigate the likelihood that one of the candidate gene loci contained the Cairn terrier-ocular melanosis locus.ResultsTwo polymorphic loci were identified within or close to each candidate gene. Genotyping of at least 10 ocular melanosis Cairn terriers for each marker showed that there was no single shared allele for either of the two polymorphic markers identified in ASIP, COMT, GPNMB, GSK3B, LYST, MC1R, MITF, SILV, TYR, TYRP1,and TYRP2. This is strong evidence to exclude each locus as the site of the ocular melanosis mutation (probability of a false exclusion calculated for each gene ranged from 1.59 × 10-4 to 1 × 10-9).ConclusionsNone of the 11 potential candidate genes selected are likely to be the gene locus for ocular melanosis in Cairn terriers.

Isolation and cultivation of canine uveal melanocytes

“…Characterization of these diseases has primarily been limited to clinical and histological descriptions of the abnormal phenotypes. More recently potential candidate genes for Cairn terrier ocular melanosis have been screened, and genomewide association studies are planned or underway for Golden retriever pigmentary uveitis (W.M. Townsend, personal communication) and for Cairn terrier ocular melanosis in our laboratory.…”

A tool set to allow rapid screening of dog families with PRA for association with candidate genes

“…In diseases with a recessive mode of inheritance, affected animals must be homozygous for the mutation, assuming a founder event, and homozygous for a linked marker in complete linkage disequilibrium (LD) with that mutation [see for a discussion of LD in this situation]. If affected dogs are not all effectively homozygous for the same allele of a tested marker (i.e., by ‘effectively homozygous’, we mean single‐step differences (tri‐, tetra‐, and penta‐STRs) or two‐step differences (diSTRs) are not counted as different alleles), the gene is excluded as being the site of the phenotype causing mutation.…”

“…To account for the most common mutation of MS (one repeat addition or deletion for tetra‐ and pentanucleotide repeats and ≤ 2 repeat units for dinucleotide repeats), dogs were not considered heterozygous for exclusion purposes if alleles only differed by these respective size changes . However, single repeat differences were included in calculations of the observed heterozygosity.…”

“…OES with an unidentified form of PRA were included to test the ability of the approach using the panel to rapidly exclude candidate genes (Table , S1). Samples were analyzed for association between marker and phenotype using a previously described method . Candidate genes were excluded as being the culprit gene when at least one of the two gene specific markers showed heterozygosity within the affected dogs of the breed being tested.…”

“…Although we have provided two markers for each gene, it is possible to genotype a single marker per gene first and follow up with the second marker, if the gene is not excluded. Probability of a false exclusion was calculated based upon the distance of the two markers from the candidate gene and assuming a recombination rate of one percent per Mb, which appears to be the average for dogs …”