title: Molecular basis of the brindled mouse mutant (Mo(br)): a murine model of Menkes disease.
abstract: The brindled mouse mutant (Mo(br)) is the closest animal model of the human genetic copper deficiency, Menkes disease, which is presumed to be due to a mutation at the X-linked mottled locus (Mo). The mutant mice are hypopigmented and die at around 15 days after birth, but can be saved by treatment with copper before the 10th postnatal day. Menkes disease has been shown to be due to mutations of the gene ATP7A which encodes P-type ATPase (referred to here as MNK). MNK is likely to function in copper efflux from cells, but the full range of its biological activity is not fully understood. The nature of the mutation in the brindled mouse is of importance in our understanding of the role of MNK and for devising treatment strategies for Menkes disease. Here we show that the brindled mouse has a deletion of two amino acids in a highly conserved, but functionally uncharacterized, region of Mnk. Comparison with the Ca ATPases suggests this region may be involved in conformational changes associated with the E1/E2 transition fundamental to the action of P-type ATPases. We also describe the first Western blot data for Mnk in tissues, and these show normal levels of Mnk in mutant and brindled kidneys but none in liver. In the kidney, immunohistochemistry demonstrated Mnk in the proximal and distal tubules, the distribution is identical in mutant and normal. This distribution is consistent with Mnk being involved in copper resorption from the urine.
authors.affiliation: Murdoch Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Grimes
authors.forename: C J
authors.initials: CJ
authors.lastname: Hearn
authors.forename: P
authors.initials: P
authors.lastname: Lockhart
authors.forename: D F
authors.initials: DF
authors.lastname: Newgreen
authors.forename: J F
authors.initials: JF
authors.lastname: Mercer
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D027682:Cation Transport Proteins; D017124:Conserved Sequence; D000073840:Copper-Transporting ATPases; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007686:Kidney Tubules, Distal / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D011993:Recombinant Fusion Proteins; D017384:Sequence Deletion
chemical_list: C486201:Atp7a protein, mouse; D002352:Carrier Proteins; D027682:Cation Transport Proteins; D011993:Recombinant Fusion Proteins; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases