Genetic mapping of the copper toxicosis locus in Bedlington terriers to dog chromosome 10, in a region syntenic to human chromosome region 2p13-p16

Abnormal hepatic copper accumulation is recognized as an inherited disorder in man, mouse, rat and dog, The major cause of hepatic copper accumulation in man is a dysfunctional ATP7B gene, causing Wilson disease (WD), Mutatio ns in the ATP7B genes have also been demonstrated in mouse and rat. The ATP 7B gene has been excluded in the much rarer human copper overload disease n on-indian childhood cirrhosis, indicating genetic heterogeneity. By investi gating the common autosomal recessive copper toxicosis (CT) in Bedlington t erriers, we have identified a new locus involved in progressive liver disea se. We examined whether the WD gene ATP7B was also causative for CT by inve stigating the chromosomal co-localization of ATP7B and C04107, using fluore scence in situ hybridization (FISH), C04107 is an anonymous microsatellite marker closely linked to CT. However, BAC clones containing ATP7B and C0410 7 mapped to the canine chromosome regions CFA22q11 and CFA10q26, respective ly, demonstrating that WD cannot be homologous to CT. The copper transport genes CTR1 and CTR2 were also excluded as candidate genes for CT since they both mapped to canine chromosome region CFA11q22.2-22.5. A transcribed seq uence identified from the C04107-containing BAC was found to be homologous to a gene expressed from human chromosome 2p13-p16, a region devoid of any positional candidate genes.