Molecular regulation of copper excretion in the liver.
Cu is an essential nutrient that is required for a broad range of cellular and molecular processes. Mammals have efficient systems to control Cu homeostasis that operate at the level of controlling uptake, distribution, sequestration and excretion of Cu. The study of diseases associated with disturbed Cu homeostasis has greatly enhanced our understanding of the molecular mechanisms involved in Cu metabolism. In man the liver is responsible for excreting excess Cu from the body by means of biliary secretion. Wilson disease is a severe human disorder characterized by Cu accumulation in the liver as a result of a deficiency in biliary Cu secretion. This disorder is caused by mutations in the gene that encodes a Cu-transporting P-type ATPase (ATP7B). The MURR1 gene was identified recently, and it was hypothesized that this gene is also essential for biliary Cu excretion and is presumed to act downstream of ATP7B. MURR1 is mutated in canine Cu toxicosis, a disorder with phenotypic characteristics similar to those of Wilson disease. MURR1 encodes a protein that is of unknown function and is without detectable sequence homology to known proteins. MURR1 is readily detected in all tissues and cell types, suggesting that it may exhibit a pleiotropic function in different organs, which may or may not be exclusively linked to Cu homeostasis. The use of genetic, biochemical and genomic tools, as well as the development of appropriate models in organisms other than dog, will allow the elucidation of the molecular and cellular function of MURR1 in relation to hepatic Cu homeostasis and biliary Cu excretion.
Wijmenga
Cisca
C
Department of Biomedical Genetics, University Medical Center, Stratenum 2.117, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands. t.n.wigmenga@med.uu.nl
Klomp
Leo W J
LW
D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000235:genetics; D000818:Animals; D001646:Bile / Q000378:metabolism; D002352:Carrier Proteins; D027682:Cation Transport Proteins / Q000235:genetics; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D004283:Dog Diseases / Q000235:genetics; D004285:Dogs; D006527:Hepatolenticular Degeneration / Q000235:genetics; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics; D009154:Mutation; D011506:Proteins / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C480519:COMMD1 protein, human; D002352:Carrier Proteins; D027682:Cation Transport Proteins; D011506:Proteins; D003300:Copper; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases