A comparison of copper-loading disease in Bedlington terriers and Wilson's disease in humans

Abstract

Eleven Bedlington terriers were found to have a mean hepatic copper concentration of 6,321 micrograms/g dry wt (normal, 200 micrograms/g dry wt) and renal copper concentration that was three or four times normal. Brain copper levels were normal in younger dogs, were elevated in two older dogs, and were 100 times normal in one dog that died of the disease. Increased concentrations of copper in the liver, kidney, and brain also characterize Wilson's disease. Erythrocyte survival was normal in three affected dogs, but serum glutamic-pyruvic transaminase levels were usually elevated. Unlike the hypoceruloplasminemia of patients with Wilson's disease, plasma ceruloplasmin activity was not only normal but was also slightly elevated in the terriers. Despite their normal or excessive ceruloplasmin, the Bedlington terriers could convert ionic 64Cu to radioceruloplasmin but did so only very slowly. These dogs accumulated significantly more 64Cu in their livers than normal, much like patients with Wilson's disease do before symptoms develop.

Copper-Induced Translocation of the Wilson Disease Protein ATP7B Independent of Murr1/COMMD1 and Rab7

“…The obvious conclusion is that Murr1/COMMD1 is required only at a later step of copper excretion, maybe in guiding copper-loaded subapical vesicles to the apical membrane, where hepatocytes can finally discharge copper into the bile. An earlier interference with copper transport seems unlikely because the loading of ceruloplasmin by ATP7B in the late Golgi is not affected even in knockout animals (Bedlington terriers 28,29 ). In a side observation, even high overexpression of Murr1/COMMD1 in HeLa cells would neither change the steady state localization of the WDP nor the copper-dependent translocation (K.H.W.…”

“…3,21,22 Certainly other proteins than ATP7B contribute to the molecular mechanism of copper excretion, and mutations or polymorphisms of these proteins might contribute to Wilson disease, maybe explaining the highly variable clinical presentation [23][24][25] and course of this disease. Canine copper toxicosis of Bedlington terriers 26 is caused by a deficiency of Murr1/COMMD1 27,28 and resembles Wilson disease, although ceruloplasmin levels are not decreased 29 and there are no evident neurological symptoms. Murr1/COMMD1 has been reported to interact physically with ATP7B.…”

A Perspective on Copper and Liver Disease in the Dog

“…44,59,60,73 This breed is afflicted with an autosomal recessive defect in copper metabolism. 36,59,60 Homozygous recessive individuals accumulate excess hepatic copper, with values rising as high as 10,000 ppm dw. Investigations have shown that the excess copper accumulates in essentially all cellular compartments of the hepatocyte.…”

“…13,71 A few older Bedlingtons have been found with increased copper levels in the brain and cornea. 60 However, these latter findings are apparently a secondary phenomenon because younger affected dogs have normal brain and cornea copper levels concomitant with elevated hepatic and renal copper. 60 Whether the elevated renal copper concentration in affected dogs is secondary to the copper accumulation in the liver or is due to an effect of the abnormal gene in the renal epithelium is not clear.…”

COMMD1: A Novel Protein Involved in the Proteolysis of Proteins

“…6,7 Copper toxicosis shows phenotypic similarities with the copper storage disorder Wilson disease (WD). 8 WD is caused by mutations in the ATP7B gene, which encodes a copper transporting P-type ATPase expressed primarily in the liver, that mediates hepatic copper excretion into bile. [9][10][11] Using positional cloning we identified a strong association between copper toxicosis in Bedlington terriers and a deletion of exon 2 of the COMMD1 (previously MURR1) gene.…”