Testing of dogs: CT

CT - Copper Toxicosis in Bedlington Terriers

(COMMD1 - associated copper toxicosis in breeding Bedlington terriers)

Copper is an essential trace element which exist in two oxidation states, therefore this element acts as a cofactor in many enzymes - e.g. Cu/Zn superoxide dismutase, a free radical scavenger, or cytochrome C oxidase as a component of metabolism in mitochondria (part of the energy releasing electron transport chain in mitochondria). Copper in its redox state is highly reactive and can be extremely toxic in excessive amounts (copper facilitates the generation of reactive oxygen species and free radicals, which damage nucleic acids, lipids and proteins). Therefore a tight regulation of copper homeostasis is required. Copper is resorbed in intestine from nutriment and excreted out of organism trough the bile (Wijmenga and Klomp 2004). Various genetic diseases of copper metabolism are characterized by either depletion or accumulation of copper.

Copper toxicosis in Bedlington Terriers is severe metabolism disease - biliary copper excretion is markedly reduced in affected dogs (Su et al.1982), and as a result copper accumulates in lysosomes of hepatocytes, eventually leading to liver cirrhosis, chronic hepatitis and premature death (Twedt et al. 1979). CT disease manifestation starts between 2 and 6 years of age. First symptoms are problems with food intake - loss of appetite, sickness and weight loss.

The main methods of diagnosing cooper toxicosis in Bedlington terriers are liver biopsy and quantitative analysis of content copper. Dogs are typically classed as normal if liver copper levels are under 400 µg/g dry weight, and as affected if copper levels exceed 850 µg/g dry weight (Some specialists consider the value of 1000 µg/g as upper limit) (Yuzbasiyan-Gurkan et al. 1993). If copper levels are between 400 and 1000 µg/g, the second biopsy is recommended at least 6 months after the original biopsy. However, it is technical-intensive and stressful procedure for tested dogs.

Copper toxicosis is an autosomal recessive disorder (Johnson et al. 1980) caused by 39,7 kb deletion in exon 2 of COMMD1 gene (copper metabolism domain containing 1; formerly MURR1). This deletion in dog chromosome 10 affects intron 1, exon 2, and intron 2.

Finding of COMMD1 mutation faciliated development of a diagnostic test, which makes  possible to bring down a frequency COMMD1-associated copper toxicosis in breeding Bedlington terriers. DNA test is reliable, predictive and non-stressful for dogs.

The test can be performed from blood sample or cheek swabs. Cheek swabs can be sampled by the owner himself - an easy and non-invasive taking of biological sample. The results of DNA test allows for breeding on healthy animals only.

The disease affects dogs with P/P (positive / positive) genotype only. Dogs with P/N (positive /negative) genotype are clinically without any symptoms. They are genetically considered carriers of the disease (heterozygotes). In offspring of two heterozygous animals following genotype distribution can be expected: 25 % N/N (healthy non-carriers), 25 % P/P (affected), and 50 % N/P (healthy carriers). Because of high risk of producing affected offspring, mating of two N/P animals (carriers) can not be recommended. DNA test is based on multiplex PCR and makes it possible to find out possible deletion and to determine possible carriers.

References:

Johnson G.F., Sternlieb I., Twedt D.C., Grushoff P.S. & Scheinberg I.(1980) Inheritance of copper toxicosis in Bedlington terriers. American Journal of Veterinary Research 41, 1865-6.

Su L.C., Owen C.A. Jr, Zollman P.E. & Hardy R.M. (1982) A defect of biliary excretion in copper-laden Bedlington terriers. American. Journal of Physiology 243, 231-6.

Pena M.M., Lee J. & Thiele D.J. (1999) A delicate balance: homeostatic control of copper uptake and distribution. Journal of Nutrition 129, 1251-60.
Forman OP, Boursnell MEG, Dunmore BJ, Stendall N, van de Sluis B, Fretwell N, Jones C, Wijmenga C, Rothuizen J, van Oost BA, Holmes NG, BinnsMM,and Jones P. (2005) Characterization of theCOMMD1(MURR1) mutation causing copper toxicosis in Bedlington terriers. Animal Genetics 36,497-501

Yuzbasiyan-Gurkan V, Brewer GJ, and Glover TW, 1999. The canine copper toxicosis locus is not syntenic with ATP7B or ATX1 and maps to a region showing homology to human 2p21. Mamm Genome 7:753-756.

Wijmenga C and Klomp LW, 2004. Molecular regulation of copper excretion in the liver. Proc Nutr Soc 1:31-39.

Twedt DC, Sternlieb I, and Gilbertson SR, 1979. Clinical, morphologic, and chemical studies on copper toxicosis of Bedlington terriers. J Am Vet Med Assoc 3:269-275.