OMIA:001071-9615 : Wilson disease in Canis lupus familiaris (dog) |
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:
Single-gene 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:
Symbol | Description | Species | Chr | Location | OMIA gene details page | Other Links |
---|---|---|---|---|---|---|
ATP7B | ATPase, Cu++ transporting, beta polypeptide | Canis lupus familiaris | 22 | NC_051826.1 (144381..208578) | ATP7B | Homologene, Ensembl , NCBI gene |
Variants
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
OMIA Variant ID | Breed(s) | Variant Phenotype | Gene | Allele | Type of Variant | Source of Genetic Variant | Reference Sequence | Chr. | g. or m. | c. or n. | p. | Verbal Description | EVA ID | Year Published | PubMed ID(s) | Acknowledgements |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
106 | Labrador Retriever (Dog) | Wilson disease | ATP7B | missense | Naturally occurring variant | CanFam3.1 | 22 | g.225112G>A | c.4151G>A | p.(R1384Q) | XM_005633831.3; XP_005633888.1; variant published as c.4358G>A / p.(R1453Q) and the variant coordinates in this table have been changed to reflect recent transcript IDs; conflicting evidence in regard to causality of this variant are reported in the literature - see https://omia.org/OMIA001071/9615/ for details | rs851958524 | 2016 | 26747866 | 30 Dec 2020: correct genomic location provided by Angelica K Kallenberg |
Cite this entry
Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2024). OMIA:001071-9615: Online Mendelian Inheritance in Animals (OMIA) [dataset]. https://omia.org/. https://doi.org/10.25910/2AMR-PV70
References
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2024 | Mutton, J., Yeomans, S., White, J. : |
Copper hepatopathies in Australian dogs. Aust Vet J 102:385-391, 2024. Pubmed reference: 38682427. DOI: 10.1111/avj.13338. | |
Nivy, R., Kuzi, S., Swinburne, J., Constantino-Casas, F., Gajanayake, I., Bruchim, Y., Berkowitz, A., Watson, P. : | |
Copper-associated chronic hepatitis in Cavalier King Charles spaniels. Vet Rec 194:e3561, 2024. Pubmed reference: 37926771. DOI: 10.1002/vetr.3561. | |
2023 | Haywood, S., Swinburne, J., Schofield, E., Constantino-Casas, F., Watson, P. : |
Copper toxicosis in Bedlington terriers is associated with multiple independent genetic variants. Vet Rec 193:e2832, 2023. Pubmed reference: 37038639. DOI: 10.1002/vetr.2832. | |
Kennedy, L., Ollier, B. : | |
Untangling the genetic traits underlying the development of copper toxicosis in Bedlington terriers. Vet Rec 193:154-156, 2023. Pubmed reference: 37594835. DOI: 10.1002/vetr.3386. | |
Wooton-Kee, C.R. : | |
Therapeutic implications of impaired nuclear receptor function and dysregulated metabolism in Wilson's disease. Pharmacol Ther 251:108529, 2023. Pubmed reference: 37741465. DOI: 10.1016/j.pharmthera.2023.108529. | |
2022 | Nakaichi, M., Iseri, T., Horikirizono, H., Itoh, H., Sunahara, H., Nemoto, Y., Itamoto, K., Tani, K. : |
Pedigree study of the heredity of copper-associated hepatitis in Dalmatians in Japan. Can Vet J 63:633-636, 2022. Pubmed reference: 35656524. | |
Nivy, R., Kuzi, S., Gajanayake, I., Berkowitz, A., Watson, P. : | |
Copper-associated chronic hepatitis in Cavalier King Charles Spaniels. In: Research Communications of the 32nd ECVIM-CA Congress Swedish Exhibition and Congress Centre, Göteborg, Sweden. Sep 2022. J Vet Intern Med 36:2455-2551, 2022. | |
Takanosu, M., Suzuki, K. : | |
Genotype frequency of ATP7A and ATP7B mutation-related copper-associated hepatitis in a Japanese guide dog Labrador retriever population. J Vet Med Sci 84:16-19, 2022. Pubmed reference: 34819411. DOI: 10.1292/jvms.21-0369. | |
2021 | Corbee, R.J., Penning, L.C. : |
COMMD1 exemplifies the power of inbred dogs to dissect genetic causes of rare copper-related disorders. Animals (Basel) 11:601, 2021. Pubmed reference: 33668783. DOI: 10.3390/ani11030601. | |
Nakaichi, M., Iseri, T., Horikirizono, H., Komine, M., Itoh, H., Sunahara, H., Nemoto, Y., Itamoto, K., Tani, K. : | |
Copper-associated hepatitis in a young Dalmatian dog in Japan. J Vet Med Sci 83:911-915, 2021. Pubmed reference: 33840721. DOI: 10.1292/jvms.21-0061. | |
2020 | Wu, X., den Boer, E.R., Vos-Loohuis, M., Steenbeek, F.G.V., Monroe, G.R., Nijman, I.J., Leegwater, P.A.J., Fieten, H. : |
Investigation of genetic modifiers of copper toxicosis in Labrador Retrievers. Life (Basel) 10:266, 2020. Pubmed reference: 33142854. DOI: 10.3390/life10110266. | |
Wu, X., Mandigers, P.J.J., Fieten, H., Leegwater, P.A. : | |
Evaluation of COMMD1 in copper toxicosis in Labrador retrievers and Dobermans. Vet J 265:105561, 2020. Pubmed reference: 33129558. DOI: 10.1016/j.tvjl.2020.105561. | |
2019 | Kruitwagen, H.S., Fieten, H., Penning, L.C. : |
Towards bioengineered liver stem cell transplantation studies in a preclinical dog model for inherited copper toxicosis. Bioengineering (Basel) 6:88, 2019. Pubmed reference: 31557851. DOI: 10.3390/bioengineering6040088. | |
Kruitwagen, H.S., Penning, L.C. : | |
Preclinical models of Wilson's disease, why dogs are catchy alternatives. Ann Transl Med 7:S71, 2019. Pubmed reference: 31179308. DOI: 10.21037/atm.2019.02.06. | |
Pindar, S., Ramirez, C. : | |
Predicting copper toxicosis: relationship between the ATP7A and ATP7B gene mutations and hepatic copper quantification in dogs. Hum Genet 138:541-546, 2019. Pubmed reference: 31062085. DOI: 10.1007/s00439-019-02010-y. | |
Wang, X., Garrick, M.D., Collins, J.F. : | |
Animal models of normal and disturbed iron and copper metabolism. J Nutr 149:2085-2100, 2019. Pubmed reference: 31504675. DOI: 10.1093/jn/nxz172. | |
Wu, X., Mandigers, P.J.J., Watson, A.L., van den Ingh, T.S.G.A.M., Leegwater, P.A.J., Fieten, H. : | |
Association of the canine ATP7A and ATP7B with hepatic copper accumulation in Dobermann dogs. J Vet Intern Med 33:1646-1652, 2019. Pubmed reference: 31254371. DOI: 10.1111/jvim.15536. | |
2018 | Reed, E., Lutsenko, S., Bandmann, O. : |
Animal models of Wilson disease. J Neurochem 146:356-373, 2018. Pubmed reference: 29473169. DOI: 10.1111/jnc.14323. | |
2016 | Fieten, H., Gill, Y., Martin, A.J., Concilli, M., Dirksen, K., van Steenbeek, F.G., Spee, B., van den Ingh, T.S., Martens, E.C., Festa, P., Chesi, G., van de Sluis, B., Houwen, R.H., Watson, A.L., Aulchenko, Y.S., Hodgkinson, V.L., Zhu, S., Petris, M.J., Polishchuk, R.S., Leegwater, P.A., Rothuizen, J. : |
The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders. Dis Model Mech 9:25-38, 2016. Pubmed reference: 26747866. DOI: 10.1242/dmm.020263. | |
Haywood, S., Boursnell, M., Loughran, M.J., Trafford, J., Isherwood, D., Liu, X., Olohan, L., Carter, S.D. : | |
Copper toxicosis in non-COMMD1 Bedlington terriers is associated with metal transport gene ABCA12. J Trace Elem Med Biol 35:83-9, 2016. Pubmed reference: 27049130. DOI: 10.1016/j.jtemb.2016.01.015. | |
Wu, X., Leegwater, P.A., Fieten, H. : | |
Canine models for copper homeostasis disorders. Int J Mol Sci 17:196, 2016. Pubmed reference: 26861285. DOI: 10.3390/ijms17020196. | |
2015 | Fieten, H., Biourge, V.C., Watson, A.L., Leegwater, P.A., van den Ingh, T.S., Rothuizen, J. : |
Dietary management of labrador retrievers with subclinical hepatic copper accumulation. J Vet Intern Med 29:822-7, 2015. Pubmed reference: 25776942. DOI: 10.1111/jvim.12574. | |
2014 | Fieten, H., Biourge, V.C., Watson, A.L., Leegwater, P.A., van den Ingh, T.S., Rothuizen, J. : |
Nutritional management of inherited copper-associated hepatitis in the Labrador retriever. Vet J 199:429-33, 2014. Pubmed reference: 24439471. DOI: 10.1016/j.tvjl.2013.12.017. | |
Fieten, H., Penning, L.C., Leegwater, P.A., Rothuizen, J. : | |
New canine models of copper toxicosis: diagnosis, treatment, and genetics. Ann N Y Acad Sci 1314:42-8, 2014. Pubmed reference: 24758744. DOI: 10.1111/nyas.12442. | |
2012 | Fieten, H., Leegwater, P.A., Watson, A.L., Rothuizen, J. : |
Canine models of copper toxicosis for understanding mammalian copper metabolism. Mamm Genome 23:62-75, 2012. Pubmed reference: 22147205. DOI: 10.1007/s00335-011-9378-7. | |
2009 | Hoffmann, G., Jones, PG., Biourge, V., van den Ingh, TS., Mesu, SJ., Bode, P., Rothuizen, J. : |
Dietary management of hepatic copper accumulation in Labrador Retrievers. J Vet Intern Med 23:957-63, 2009. Pubmed reference: 19627473. DOI: 10.1111/j.1939-1676.2009.0352.x. | |
2007 | Haywood, S., Jones, R. : |
Hunt for a second copper toxicosis gene. Vet Rec 160:743, 2007. Pubmed reference: 17526900. DOI: 10.1136/vr.160.21.743. | |
2006 | Hoffmann, G., van den Ingh, TS., Bode, P., Rothuizen, J. : |
Copper-associated chronic hepatitis in Labrador Retrievers. J Vet Intern Med 20:856-61, 2006. Pubmed reference: 16955809. DOI: 10.1892/0891-6640(2006)20[856:cchilr]2.0.co;2. | |
2002 | Webb, C.B., Twedt, D.C., Meyer, D.J. : |
Copper-associated liver disease in Dalmatians: A review of 10 dogs (1998-2001) Journal of Veterinary Internal Medicine 16:665-668, 2002. Pubmed reference: 12465762. | |
2001 | Nanji, M., Coronado, V.A., Cox, D.W. : |
ATP6H, a subunit of vacuolar ATPase involved in metal transport: evaluation in canine copper toxicosis Mammalian Genome 12:617-621, 2001. Pubmed reference: 11471056. | |
1999 | Noaker, L.J., Washabau, R.J., Detrisac, C.J., Heldmann, E., Hendrick, M.J. : |
Copper associated acute hepatic failure in a dog Journal of the American Veterinary Medical Association 214:1502-1506, 1999. Pubmed reference: 10340076. | |
1998 | Brewer, G.J. : |
Wilson disease and canine copper toxicosis American Journal of Clinical Nutrition 67:S1087-S1090, 1998. | |
Ubbink, G.J., Vandebroek, J., Hazewinkel, H.A.W., Rothuizen, J. : | |
Cluster analysis of the genetic heterogeneity and disease distributions in purebred dog populations Veterinary Record 142:209-213, 1998. Pubmed reference: 9533291. | |
1996 | Thornburg, L.P., Rottinghaus, G., Dennis, G., Crawford, S. : |
The relationship between hepatic copper content and morphologic changes in the liver of West Highland White terriers Veterinary Pathology 33:656-661, 1996. Pubmed reference: 8952024. | |
1995 | Rolfe, D.S., Twedt, D.C. : |
Copper-associated hepatopathies in dogs Veterinary Clinics of North America - Small Animal Practice 25:399-417, 1995. | |
1992 | Brewer, G.J., Dick, R.D., Schall, W., Yuzbasiyan-Gurkan, V., Mullaney, T.P., Pace, C., Lindgren, J., Thomas, M., Padgett, G. : |
Use of zinc acetate to treat copper toxicosis in dogs Journal of the American Veterinary Medical Association 201:564-568, 1992. Pubmed reference: 1517130. | |
1991 | Riordan, J.F., Stockert, R.J., Vallee, B.L., Morell, A.G., Sternlieb, I. : |
Purification of canine hepatic lysosomal copper- metallothionein. Metallobiochemistry, Pt B 205:286-291, 1991. | |
1988 | Haywood, S., Rutgers, H.C., Christian, M.K. : |
Hepatitis and copper accumulation in Skye terriers Veterinary Pathology 25:408-414, 1988. Pubmed reference: 3212885. | |
1987 | Howell, J.M., Wiener, G., Gawthorne, J.M. : |
The genetics of copper metabolism in animals and man :45-61, 1987. | |
1986 | Thornburg, L.P., Shaw, D., Dolan, M., Raisbeck, M., Crawford, S., Dennis, G.L., Olwin, D.B. : |
Hereditary copper toxicosis in West Highland white terriers Veterinary Pathology 23:148-154, 1986. Pubmed reference: 3962081. |
Edit History
- Created by Frank Nicholas on 05 Oct 2005
- Changed by Frank Nicholas on 29 Sep 2011
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