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

Abstract

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). Mutations in the ATP7B genes have also been demonstrated in mouse and rat. The ATP7B gene has been excluded in the much rarer human copper overload disease non-Indian childhood cirrhosis, indicating genetic heterogeneity. By investigating the common autosomal recessive copper toxicosis (CT) in Bedlington terriers, we have identified a new locus involved in progressive liver disease. We examined whether the WD gene ATP7B was also causative for CT by investigating the chromosomal co-localization of ATP7B and C04107, using fluorescence in situ hybridization (FISH). C04107 is an anonymous microsatellite marker closely linked to CT. However, BAC clones containing ATP7B and C04107 mapped to the canine chromosome regions CFA22q11 and CFA10q26, respectively, 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 sequence 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.

Single-Nucleotide-Polymorphism-Based Association Mapping of Dog Stereotypes

“…Segregation in planned crosses or within a breed population can be used to identify loci for simple and complex phenotypes. This approach takes advantage of the large LD distances that can be attributed to founder effects and bottlenecks (for example, Mignot et al 1991;Acland et al 1998Acland et al , 1999Lingaas et al 1998;Van de Sluis et al 1999;Jonasdottir et al 2000;Chase et al 2005aChase et al , 2006Todhunter et al 2005). 2.…”

The canine genome

“…The identification of the MURR1 gene associated with copper toxicosis in Bedlington Terriers (van De Sluis et al 2002) provides an excellent example. Contrary to expectation, this disease did not map to the portion of the canine genome analogous to the Wilson's disease locus in humans (Yuzbasiyan-Gurkan et al 1997;van de Sluis et al 1999). Analysis of the human homolog of MURR1 in Wilson's disease patients has subsequently proven provocative, as those who carry particular sequence variants appear to present with earlier onset disease (Stuehler et al 2004), suggesting that the two genes or their products interact to accelerate disease.…”

The Mouse Murr1 Gene Is Imprinted in the Adult Brain, Presumably Due to Transcriptional Interference by the Antisense-Oriented U2af1-rs1 Gene

“…The cDNA sequence has been submitted to the DDBJ database under accession numbers D85430 (27) and AB104816. Although the function of the protein has not yet been analyzed in mice, the homologue in the dog was reported to be involved in copper metabolism (41,42).…”