The ubiquitously expressed MURR1 protein is absent in canine copper toxicosis

Background/Aims: Copper toxicosis (CT) in Bedlington terriers is an autosomal recessive disorder characterized by massive lysosomal copper accumulation in livers of affected dogs, and a defect in the biliary excretion of this metal. We propose that MURR1, the gene defective in canine CT, has a role...

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Bibliographic Details
Published in:Journal of hepatology 2003-11, Vol.39 (5), p.703-709
Main Authors: Klomp, Adriana E.M, van de Sluis, Bart, Klomp, Leo W.J, Wijmenga, Cisca
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing
Animals
Bedlington terrier
Canine copper toxicosis
Carrier Proteins
Cell Line
Copper - metabolism
Copper accumulation
Dog Diseases - genetics
Dog Diseases - metabolism
Dogs
Female
Gene Deletion
Genetic Diseases, Inborn - veterinary
Humans
Immune Sera
Liver
Liver - metabolism
Mice
MURR1
Proteins - genetics
Proteins - metabolism
Subcellular Fractions - metabolism
Vesicular compartment
Wilson disease
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Summary:Background/Aims: Copper toxicosis (CT) in Bedlington terriers is an autosomal recessive disorder characterized by massive lysosomal copper accumulation in livers of affected dogs, and a defect in the biliary excretion of this metal. We propose that MURR1, the gene defective in canine CT, has a role in the regulation of copper excretion into bile during copper overload. Methods: Polyclonal antibodies raised against full-length recombinant human MURR1 were used for immunoblot analysis and indirect immunofluorescence studies. Results: Using Western blot analysis, these antibodies abundantly detected MURR1 as a 23 kDa protein in liver extracts of mice and dogs, but MURR1 was undetectable in the livers of affected Bedlington terriers. MURR1 was also detected in different tissues and cell lines; in cell lines the protein was found both in cytosol and membrane preparations. Consistent with this observation, indirect immunofluorescence staining revealed that in some cells MURR1 was associated with a vesicular compartment diffusely localized throughout the cell. Conclusions: The genomic deletion in MURR1 results in complete absence of MURR1 protein. Based on the unanticipated subcellular localization, our results suggest a role for MURR1 in the regulation of vesicular copper sequestration during copper overload.
ISSN:0168-8278
1600-0641
DOI:10.1016/S0168-8278(03)00380-5