title: Mutation in the CPC motif-containing 6th transmembrane domain affects intracellular localization, trafficking and copper transport efficiency of ATP7A protein in mosaic mutant mice--an animal model of Menkes disease.
abstract: Copper is an essential micronutrient for all living organisms. ATP7A protein is a copper-transporting ATPase which plays a vital role in the maintenance of cellular copper homeostasis in mammals. This protein is retained within the trans-Golgi network, but after binding copper it can be translocated to the cell membrane to participate in the efflux of excess Cu. Mutation of the ATP7A gene in humans results in the severe neurodegenerative disorder, Menkes disease. The mouse ATP7A homolog encodes a protein that plays the same role in copper transport. Mosaic mutant mice display a lethal phenotype which resembles Menkes disease, although the underlying molecular defect has not been characterized until now. In the present study we identified a G to C nucleotide exchange in exon 15 of the Atp7a gene in mosaic mutants, which resulted in an arginine to proline substitution in the highly conserved 6th transmembrane domain of the ATP7A protein. This mutated protein was mislocalized in kidney cells isolated from mosaic mutant mice, and following exposure of these cells to increased copper concentrations it was not translocated to the plasma membrane. Disturbance of ATP7A function in mosaic mice results in increased copper accumulation in the small intestine and kidneys, and in Cu deficiency in the brain, liver and heart. Mouse models of Menkes disease belong to the mottled mutant group. The mosaic mutant represents another interesting animal model for Menkes disease that will be of value in research on copper metabolism and transport in mammals.
authors.affiliation: Department of Genetics and Evolution, Institute of Zoology, Jagiellonian University, Ingardena 6, Gronostajowa 9, 30-387 Kraków, Poland. malgorzata.lenartowicz@gmail.com
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Lenartowicz
authors.forename: Paweł
authors.initials: P
authors.lastname: Grzmil
authors.forename: Moneef
authors.initials: M
authors.lastname: Shoukier
authors.forename: Rafał
authors.initials: R
authors.lastname: Starzyński
authors.forename: Marcin
authors.initials: M
authors.lastname: Marciniak
authors.forename: Paweł
authors.initials: P
authors.lastname: Lipiński
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D001693:Biological Transport, Active; D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D007684:Kidney Tubules / Q000166:cytology / Q000378:metabolism; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009030:Mosaicism; D009154:Mutation; D009928:Organ Specificity; D017434:Protein Structure, Tertiary
chemical_list: C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D003300:Copper; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases