In other species: domestic cat , pig , taurine cattle , sheep

Categories: Liver/biliary system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 277900 (trait) , 606882 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0010200: Wilson disease

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2016

Cross-species summary: A disorder of copper metabolism, due to a deficiency of ceruloplasmin, which forms a complex with copper. The excess copper is deposited in the brain (causing mental retardation) or the liver (causing jaundice and cirrhosis).

Species-specific name: copper toxicosis; copper storage disease, copper-associated hepatitis, copper-associated chronic hepatitis (CACH)

Species-specific symbol: CT

Species-specific description: Excessive copper deposition leading to copper toxicosis is a complex genetic disorder that can lead to copper-associated chronic hepatitis. In Labrador retrievers accumulation of hepatic copper levels has been partly explained by a variant in the ATP7B gene (c.4358G>A) and proposed genetic modifiers of copper toxicosis in the ATP7A and RETN gene (see 'OMIA 002608-9615 Modifier of copper toxicosis, ATP7A-related in Canis lupus familiaris' and OMIA 002609-9615 Modifier of copper toxicosis, RETN-related in Canis lupus familiaris'). For information on a different form of copper toxicosis in Bedlington Terriers due to variants in the COMMD1 gene see: 'OMIA001988-9615 : Copper toxicosis, COMMD1-related'

Molecular basis: Fieten et al. (2016): "The amino acid substitution ATP7B:p.Arg1453Gln was associated with copper accumulation . . . We identified the Labrador retriever as the first natural, non-rodent model for ATP7B-associated copper toxicosis" Wu et al. (2019) concluded that "The ATP7B:c.4358G>A variant could be a contributor to hepatic copper accumulation underlying the risk of development of copper-associated hepatitis in breeds other than the Labrador Retriever." Wu et al. (2020) "investigated the possible involvement of COMMD1 in the multifactorial aetiology of copper toxicosis in Labrador retrievers and Dobermans" and 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) "The mutation in ATP7B first identified in Labrador retrievers is widespread in Bedlington terriers and appears to play a role in CT [copper toxicosis] in the breed. Its role may have become more important as the frequency of the COMMD1 deletion was reduced. ... [The authors] report the frequency of the ATP7B:c.4358G>A allele [OMIA variant ID:106] in a large number of dogs from a variety of breeds in the UK. Analysis of WGS data from 144 dogs of 66 different breeds indicates that the ATP7B:c.4358G>A allele is a common variant and segregates in multiple dog breeds, including many that have not been reported to have an increased prevalence of CT. Of note, two out of four crossbreeds were heterozygotes, and one Cavalier King Charles Spaniel was homozygous, a breed very recently reported with copper storage disease in the UK and Israel [Nivy et al. 2022]. This suggests that if the allele is in fact a risk factor for CT, additional risk factors (genetic or environmental) likely play a role in the development of disease, and these additional risk factors might vary between breeds. Until additional, breed-specific risk factors are better understood, it is unwise to use selection against ATP7B:c.4358G>A as a means to reduce the prevalence of CT in any breed for which association with disease has not been demonstrated." Nivy et al. (2024) investigated copper-associated chronic hepatitis (CuCH) in 13 affected Cavalier King Charles spaniels (CKCS) and eight unaffected controls. "All affected dogs were homozygous negative for the COMMD1 and ATP7A variants but homozygous positive or heterozygous for the ATP7B variant reported in LRs [Labradors], alluding to a possible genetic breed predisposition. ... When control dogs with a negative copper staining were tested for the ATP7B variant, one was homozygous negative, three were homozygous positive and four were heterozygous. ... the occurrence of the ATP7B variant in the control dogs demonstrates that the ATP7B variant is not singularly causative in the pathogenesis of CuCH in CKCS."

Breeds: Bedlington Terrier (Dog) (VBO_0200137), Cavalier King Charles Spaniel (Dog) (VBO_0200309), Dalmatian (Dog) (VBO_0200427), Doberman Pinscher (Dog) (VBO_0200442), Labrador Retriever (Dog) (VBO_0200800).
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: