Categories: Liver/biliary system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 607238 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2005

Cross-species summary: Renamed from 'Wilson disease, COMMD1 type' [10/01/2023]

Species-specific name: copper toxicosis, atypical form of Wilson disease

Species-specific symbol: CT

Species-specific description: Bedlington terrier copper toxicosis has been reported to be caused by a homozygous exon deletion in COMMD1 (Forman et al., 2005). However, copper toxicosis has since been diagnosed in Bedlington terriers lacking the COMMD1 deletion, and in these dogs the disease has been associated with two splice variants in the ABCA12 gene (Haywood et al. 2016) and a variant in the ATP7B gene that has been proposed as causal variant for Wilson disease (see OMIA:001071-9615 : Wilson disease in Canis lupus familiaris) (Haywood et al., 2023). Labrador retriever copper toxicosis is associated with a missense mutation in ATP7B (see OMIA:001071-9615 : Wilson disease in Canis lupus familiaris), and with a protective mutation in ATP7A (see OMIA:002608-9615 : Modifier of copper toxicosis, ATP7A-related in Canis lupus familiaris).

Mapping: Yuzbasiyan-Gurkan et al. (1997) performed a genome scan with 213 microsatellites on Bedlington Terrier families comprising 77 animals, 25 of which were affected. One closely linked (0 cM) microsatellite (C04107) was identified. van der Sluis et al. (1999) FISH-mapped a BAC clone containing this microsatellite to a metaphase spread of canine chromosomes, showing that the marker, and hence the disorder gene, is on canine chromosome CFA10q26, in a region of conserved synteny with human chromosome HSA2p13–p16. Detailed analysis of this BAC revealed sequence highly similar to that of an exon of the MURR1 gene of humans and mouse. Radiation-hybrid mapping of this gene revealed it to be located in HSA2p13–p16, i.e. the region showing conserved synteny with the region of CFA10 that includes the canine disorder gene. Haywood et al. (2016) reported that the causal gene for non-COMMD1 Bedligton Terriers with this disorder maps to chromosome 30 in a region that "contains the ABCA12 gene which bears a close functional relationship to ATP-ase 7B responsible for Wilson's disease in man."

Markers: Even though the chromosomal location of microsatellite C04107 was not then known, it proved to be a very useful marker for identifying carriers (Holmes et al., 1998).

Molecular basis: van der Sluis et al. (2002) refined "the localization of the copper toxicosis gene to a region of <500 kb [in CFA10q26] by linkage disequilibrium mapping. While screening genes and expressed sequence tags in this region for mutations we found that exon 2 of the MURR1 gene is deleted in both alleles of all affected Bedlington terriers and in single alleles in obligate carriers." Detailed study of this deletion enabled Forman et al. (2005) to report that the deletion "breakpoints were positioned at 65.3091 and 65.3489 Mb of dog chromosome 10, in intron 1 and intron 2 of COMMD1 respectively, a deletion of 39.7 kb. The two breakpoints share sequence homology suggesting that homologous recombination may have been responsible for the deletion". Wu et al. (2020) concluded that "COMMD1 did not play a major role in the aetiology of copper associated hepatitis in Labrador retrievers and Dobermans" Haywood et al. (2023) “Liver and DNA samples from 24 COMMD1 affected and 10 unaffected Bedlingtons were assessed for copper and genetic variants.” The authors tested for variants in COMMD1 (OMIA variant ID:643), ATP7B (OMIA variant ID:106), ATP7A (OMIA variant ID:107) and 2 SNPs in ABCA12 (Haywood et al., 2016). “All affected dogs were homozygous for either the COMMD1 deletion or the ATP7B variant. … Two of the 10 normal dogs were wild type for all genes investigated, none was homozygous for the COMMD1 deletion and only three were homozygous for the ATP7B variant. … All dogs only carried the ATP7A:c.980C allele and were therefore negative for the protective mutation. … The two ABCA12 SNPs were seen to be widespread in Bedlington terriers and there was no obvious difference between affected and control dogs. … The results suggest that ATP7B mutations may play an important role in CT in COMMD1+/+ Bedlington terriers because of the high frequency of the mutated allele in affected dogs compared with control normal Bedlington terrier dogs, including homozygous ATP7B:c.4358A in all but one affected COMMD1+/+ dog. … The role of the ABCA12 SNPs remains unclear. It is likely that CT in Bedlington terriers and other breeds is a polygenic disease involving an interaction between a number of genes involved in copper transport and dietary copper intake.”

Clinical features: Su et al. (1982): Bedlington terriers with copper toxicosis initially present clinically normal despite increases in hepatic and renal and later brain copper levels. "The dogs's ceruloplasmin level is reported to be normal, Kayser-Fleischer rings have not been observed, and neurological manifestations are lacking. However, owners of these dogs have noted significant personality changes preceding symptoms of the hepatic disease" which occurs as disease is progressing. Favier et al. (2012) report longitudinal follow up of 5 COMMD-1 deficient Bedlington terriers until the age of 42 month: "During the entire follow-up period dogs showed no abnormalities at physical examination. Serum ALT was significantly increased at 24, 36, and 42 months of age (2–3-fold), whereas serum AP significantly increased at 18 and 42 months of age. During the 42 months follow-up period, bile acids and albumin remained within reference limits ... ." Acute clinical signs of hepatic disease in older animals include depression, vomiting, anorexia, prolonged capillary refill time, weight loss and jaundice. Chronic courses involve less severe signs but can include ascites, polydipsic and behavioural changes due to hepatic encephalopathy (Washabau, 2013; Herrtage et al., 1987). IT thanks DVM student Xinlin Dong, who provided the basis of this contribution in May 2023.

Pathology: An elevated hepatic copper concentration (normal mean is 206 ± 56 μg/g dry weight of liver in Bedlington terriers) with age is the key pathological feature found by liver biopsy and quantitative analysis. In the early stage, the hepatic copper concentration is between 400 and 1500 μg/g, and copper mainly accumulates in zone 3 with unremarkable histopathological founds. When the hepatic copper concentration is between 1500 and 2000 μg/g, accumulated copper is also found in zone 2 and zone 1 with focal hepatitis on biopsy. Chronic hepatitis or cirrhosis appears on biopsy when the hepatic copper concentration exceeds 2000 μg/g (Washabau, 2013). The longitudinal study by Favier et al. (2023) reports that at "six months of age all dogs showed a moderate centrilobular hepatic copper accumulation; however no evidence of copper laden Kupffer cells ... or other evidence of hepatitis was observed at this stage ... . At 12 months of age all animals had extensive copper accumulation diffuse throughout the lobules and in two animals a mild hepatitis was present. At 18 months all dogs showed a slight to mild hepatitis. Although there was some individual variation, the activity of hepatitis progressed to mild and moderate at older age (>24 months) in all dogs." IT thanks DVM student Xinlin Dong, who provided the basis of this contribution in May 2023.

Prevalence: Haywood et al. (2023) "The prevalence [of copper toxicosis] in this breed was very high in the 1970s and 1980s, ranging from 26% to 46% in different Bedlington terrier populations (Kelly et al., 1984). ... The COMMD1 deletion is no longer the predominant cause of CT in Bedlington terriers. Testing for the deletion is still indicated prior to breeding, because it remains present in the breed, but copper storage disease cannot be ruled out by demonstrating that a dog is COMMD1+/+. Liver biopsies are necessary to rule this out."

Genetic testing: One of the many laboratories offering a DNA test for this disorder is Dr. Van Haeringen Laboratorium B.V: www.vhlgenetics.com

Breed: Bedlington Terrier (Dog) (VBO_0200137).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: