• 1.

    Festa RA, Thiele DJ. Copper: an essential metal in biology. Curr Biol. 2011;21(21):R877R883.

  • 2.

    Harris ED. Cellular copper transport and metabolism. Annu Rev Nutr. 2000;20:291310.

  • 3.

    Suzuki KT, Rui M, Ueda J-I, Ozawa T. Production of hydroxyl radicals by copper-containing metallothionein: roles as prooxidant. Toxicol Appl Pharmacol. 1996;141(1):231237.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Vincent AM, Sordillo LM, Smedley RC, Gandy JC, Brown JL, Langlois DK. Peripheral markers of oxidative stress in Labrador Retrievers with copper-associated hepatitis. J Small Anim Pract. 2021;62(10):866873.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Dirksen K, Fieten H. Canine copper-associated hepatitis. Vet Clin North Am Small Anim Pract. 2017;47(3):631644.

  • 6.

    Webster CRL, Center SA, Cullen JM, et al. ACVIM consensus statement on the diagnosis and treatment of chronic hepatitis in dogs. J Vet Intern Med. 2019;33(3):11731200.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Langlois DK, Smedley RC, Schall WD, Kruger JM. Acquired proximal renal tubular dysfunction in 9 Labrador Retrievers with copper-associated hepatitis (2006–2012). J Vet Intern Med. 2013;27(3):491499.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Yuzbasiyan-Gurkan V, Blanton SH, Cao Y, et al. Linkage of a microsatellite marker to the canine copper toxicosis locus in Bedlington Terriers. Am J Vet Res. 1997;58(1):2327.

    • Search Google Scholar
    • Export Citation
  • 9.

    Thornburg LP, Rottinghaus G, Dennis G, Crawford S. The relationship between hepatic copper content and morphologic changes in the liver of West Highland White Terriers. Vet Pathol. 1996;33(6):656661.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Webb CB, Twedt DC, Meyer DJ. Copper-associated liver disease in Dalmatians: a review of 10 dogs (1998–2001). J Vet Intern Med. 2002;16(6):665668.

    • Search Google Scholar
    • Export Citation
  • 11.

    Mandigers PJJ, van den Ingh TSGAM, Bode P, Teske E, Rothuizen J. Association between liver copper concentration and subclinical hepatitis in Dobermann Pinschers. J Vet Intern Med. 2004;18(5):647650.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Hoffmann G, van den Ingh TSGAM, Bode P, Rothuizen J. Copper-associated chronic hepatitis in Labrador Retrievers. J Vet Intern Med. 2006;20(4):856861.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    van De Sluis B, Rothuizen J, Pearson P, van Oost BA, Wijmenga C. Identification of a new copper metabolism gene by positional cloning in a purebred dog population. Hum Mol Genet. 2002;11(2):165173.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Wu X, Mandigers PJJ, Fieten H, Leegwater PA. Evaluation of COMMD1 in copper toxicosis in Labrador Retrievers and Dobermans. Vet J. 2020;265):105561. doi:10.1016/j.tvjl.2020.105561

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Association of American Feed Control Officials. Official Publication. Association of Feed Control Officials; 1997.

  • 16.

    Czarnecki-Maulden G, Chausow D. Copper bioavailability and requirement in the dog: comparison of copper oxide and copper sulfate. FASEB J. 1993;7(3-4):A305.

    • Search Google Scholar
    • Export Citation
  • 17.

    Strickland JM, Buchweitz JP, Smedley RC, et al. Hepatic copper concentrations in 546 dogs (1982–2015). J Vet Intern Med. 2018;32(6):19431950.

  • 18.

    Johnston AN, Center SA, McDonough SP, Wakshlag JJ, Warner KL. Hepatic copper concentrations in Labrador Retrievers with and without chronic hepatitis: 72 cases (1980–2010). J Am Vet Med Assoc. 2013;242(3):372380.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Center SA, Richter KP, Twedt DC, Wakshlag JJ, Watson PJ, Webster CRL. Is it time to reconsider current guidelines for copper content in commercial dog foods? J Am Vet Med Assoc. 2021;258(4):357364.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Fieten H, Gill Y, Martin AJ, et al. The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador Retrievers: a new canine model for copper-metabolism disorders. Dis Model Mech. 2016;9(1):2538.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Wu X, Mandigers PJJ, Watson A, van den Ingh TSGAM, Leegwater PAJ, Fieten H. Association of canine ATP7A and ATP7B with hepatic copper accumulation in Dobermann dogs. J Vet Intern Med. 2019;33(4):16461652.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Kim B-E, Nevitt T, Thiele DJ. Mechanisms for copper acquisition, distribution and regulation. Nat Chem Biol. 2008;4(3):176185.

  • 23.

    Wu X, den Boer ER, Vos-Loohuis M, et al. Investigation of genetic modifiers of copper toxicosis in Labrador Retrievers. Life (Basel). 2020;10(11):266. doi:10.3390/life10110266

    • Search Google Scholar
    • Export Citation
  • 24.

    CT - copper toxicosis (Labrador type). VetGen. Accessed December 26, 2021. https://www.vetgen.com/canine-ct-lab.html

  • 25.

    Copper toxicosis Labrador Retriever ATP7B (CT-LAB-B). GenSol Diagnostics. Accessed December 26, 2021. https://www.gensoldx.com/product/copper-toxicosis-labrador-retriever-ATP7B-ct-lab-b/

    • Search Google Scholar
    • Export Citation
  • 26.

    Copper toxicosis (Labrador Retriever type). Paw Print Genetics. Accessed December 26, 2021. https://www.pawprintgenetics.com/products/tests/details/195/

    • Search Google Scholar
    • Export Citation
  • 27.

    Ubbink GJ, Van den Ingh TS, Yuzbasiyan-Gurkan V, Teske E, Van de Broek J, Rothuizen J. Population dynamics of inherited copper toxicosis in Dutch Bedlington Terriers (1977–1997). J Vet Intern Med. 2000;14(2):172176.

    • Search Google Scholar
    • Export Citation
  • 28.

    Pindar S, Ramirez C. Predicting copper toxicosis: relationship between the ATP7A and ATP7B gene mutations and hepatic copper quantification in dogs. Hum Genet. 2019;138(5):541546.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    van den Ingh TSGAM, Van Winkle T, Cullen JM, et al. Morphological classification of parenchymal disorders of the canine and feline liver: hepatocellular death, hepatitis and cirrhosis. WSAVA Standards for Clinical and Histological Diagnosis of Canine and Feline Liver Diseases. Saunders Elsevier; 2006:85101.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Center SA, McDonough SP, Bogdanovic L. Digital image analysis of rhodanine-stained liver biopsy specimens for calculation of hepatic copper concentrations in dogs. Am J Vet Res. 2013;74(12):14741480.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Harro CC, Smedley RC, Buchweitz JP, Langlois DK. Hepatic copper and other trace mineral concentrations in dogs with hepatocellular carcinoma. J Vet Intern Med. 2019;33(5):21932199.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32.

    Johnston AN, Center SA, McDonough SP, Warner KL. Influence of biopsy specimen size, tissue fixation, and assay variation on copper, iron, and zinc concentrations in canine livers. Am J Vet Res. 2009;70(12):15021511.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33.

    Thornburg LP. A perspective on copper and liver disease in the dog. J Vet Diagn Invest. 2000;12(2):101110.

  • 34.

    Madsen E, Gitlin JD. Copper and iron disorders of the brain. Annu Rev Neurosci. 2007;30:317337.

  • 35.

    Holcomb IN, Kabakoff RC, Chan B, et al. FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J. 2000;19(15):40464055.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    Shen C, Zhao CY, Wang W, et al. The relationship between hepatic resistin overexpression and inflammation in patients with nonalcoholic steatohepatitis. BMC Gastroenterol. 2014;14):39. doi:10.1186/1471-230X-14-39

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Bertolani C, Sancho-Bru P, Failli P, et al. Resistin as an intrahepatic cytokine: overexpression during chronic injury and induction of pro inflammatory actions in hepatic stellate cells. Am J Pathol. 2006;169(6):20422053.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.

    O’Neill S, Drobatz K, Satyaraj E, Hess R. Evaluation of cytokines and hormones in dogs before and after treatment of diabetic ketoacidosis and in uncomplicated diabetes mellitus. Vet Immunol Immunopathol. 2012;148(3-4):276283.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39.

    Acquarone E, Monacelli F, Borghi R, Nencioni A, Odetti P. Resistin: a reappraisal. Mech Ageing Dev. 2019;178:4663.

  • 40.

    Shih JL, Keating JH, Freeman LM, Webster CR. Chronic hepatitis in Labrador Retrievers: clinical presentation and prognostic factors. J Vet Intern Med. 2007;21(1):3339.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41.

    Smedley R, Mullaney T, Rumbeiha W. Copper-associated hepatitis in Labrador Retrievers. Vet Pathol. 2009;46(3):484490.

  • 42.

    Fieten H, Hooijer-Nouwens BD, Biourge VC, et al. Association of dietary copper and zinc levels with hepatic copper and zinc concentration in Labrador Retrievers. J Vet Intern Med. 2012;26(6):12741280.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43.

    Riera-Romo M. COMMD1: a multifunctional regulatory protein. J Cell Biochem. 2018;119(1):3451.

  • 44.

    Muller T, Feichtinger H, Berger H, Muller W. Endemic Tyrolean infantile cirrhosis: an ecogenetic disorder. Lancet. 1996;347(9005):877880.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45.

    Nayak NC, Chitale AR. Indian childhood cirrhosis (ICC) & ICC-like diseases: the changing scenario of facts versus notions. Indian J Med Res. 2013;137(6):10291042.

    • Search Google Scholar
    • Export Citation
  • 46.

    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. 2022;84(1):1619.

    • Crossref
    • Search Google Scholar
    • Export Citation

Advertisement

ATP7A, ATP7B, and RETN genotypes in Labrador Retrievers with and without copper-associated hepatopathy

View More View Less
  • 1 Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI
  • | 2 Veterinary Diagnostic Laboratory, College of Veterinary Medicine, Michigan State University, East Lansing, MI
  • | 3 Department of Microbiology and Molecular Genetics, College of Veterinary Medicine, Michigan State University, East Lansing, MI

Abstract

OBJECTIVE

To determine the frequency of previously reported coding variants in the ATP7A, ATP7B, and RETN genes in a US population of Labrador Retrievers and to explore potential associations of these genotypes with pathologic hepatic copper accumulation.

SAMPLE

Archived hepatic specimens from 90 Labrador Retrievers collected between 2013 and 2021.

PROCEDURES

The Michigan State University Veterinary Diagnostic Laboratory database was searched to identify archived tissues from Labrador Retrievers that had undergone hepatic histopathologic assessment. Cases were classified into control, copper-associated hepatopathy (CAH), and intermediate populations on the basis of histopathologic features and hepatic copper accumulation. The DNA was extracted from archived tissues and genotyped for reported variants in the 3 genes. Allele frequencies were determined, and associations of genotypes with CAH status were evaluated.

RESULTS

29 control dogs, 45 CAH dogs, and 16 intermediate dogs were included in the study. The overall ATP7A and RETN variant allele frequencies were 30% and 13%, respectively, and were not significantly different among control, CAH, and intermediate populations. The ATP7B variant allele frequency was significantly higher in the CAH population (30%) as compared to the control population (13%). However, 21 of 45 (47%) CAH dogs did not have an ATP7B variant allele whereas 7 of 28 (25%) control dogs did have an ATP7B variant allele.

CLINICAL RELEVANCE

Study results supported a contributory role for the ATP7B variant in CAH pathogenesis in Labrador Retrievers. However, the application of genetic testing in a clinical setting is complicated by genotypic variability within healthy and diseased dogs.

Abstract

OBJECTIVE

To determine the frequency of previously reported coding variants in the ATP7A, ATP7B, and RETN genes in a US population of Labrador Retrievers and to explore potential associations of these genotypes with pathologic hepatic copper accumulation.

SAMPLE

Archived hepatic specimens from 90 Labrador Retrievers collected between 2013 and 2021.

PROCEDURES

The Michigan State University Veterinary Diagnostic Laboratory database was searched to identify archived tissues from Labrador Retrievers that had undergone hepatic histopathologic assessment. Cases were classified into control, copper-associated hepatopathy (CAH), and intermediate populations on the basis of histopathologic features and hepatic copper accumulation. The DNA was extracted from archived tissues and genotyped for reported variants in the 3 genes. Allele frequencies were determined, and associations of genotypes with CAH status were evaluated.

RESULTS

29 control dogs, 45 CAH dogs, and 16 intermediate dogs were included in the study. The overall ATP7A and RETN variant allele frequencies were 30% and 13%, respectively, and were not significantly different among control, CAH, and intermediate populations. The ATP7B variant allele frequency was significantly higher in the CAH population (30%) as compared to the control population (13%). However, 21 of 45 (47%) CAH dogs did not have an ATP7B variant allele whereas 7 of 28 (25%) control dogs did have an ATP7B variant allele.

CLINICAL RELEVANCE

Study results supported a contributory role for the ATP7B variant in CAH pathogenesis in Labrador Retrievers. However, the application of genetic testing in a clinical setting is complicated by genotypic variability within healthy and diseased dogs.

Supplementary Materials

    • Supplementary Appendix S1 (PDF 148 KB)

Contributor Notes

Corresponding author: Dr. Langlois (langlo21@msu.edu) or Dr. Yuzbasiyan-Gurkan (vygsu@msu.edu)

Dr. Langlois and Mr. Nagler were both first authors for this study.