ATP7A is important for regulating copper levels in the body. This protein is found in most tissues, but it is absent from the liver. In the small intestine, the ATP7A protein helps control the absorption of copper from food. In other organs and tissues, the ATP7A protein has a dual role and shuttles between two locations within the cell. The protein normally resides in a cell structure called the Golgi apparatus, which modifies and transports newly produced enzymes and other proteins. Here, the ATP7A protein supplies copper to certain enzymes that are critical for the structure and function of bone, skin, hair, blood vessels, and the nervous system. If copper levels in the cell environment are elevated, however, the ATP7A protein moves to the cell membrane and eliminates excess copper from the cell.
Menkes syndrome is caused by mutations in the ATP7A gene. Researchers have identified more than 100 ATP7A mutations that cause Menkes syndrome and occipital horn syndrome, the milder form of Menkes syndrome. Many of these mutations delete part of the gene and are predicted to produce a shortened ATP7A protein that is unable to transport copper. Other mutations insert additional DNA building blocks (base pairs) or use the wrong building blocks, which leads to ATP7A proteins that do not function properly.
The altered proteins that result from ATP7A mutations impair the absorption of copper from food, fail to supply copper to certain enzymes, or get stuck in the cell membrane, unable to shuttle back and forth from the Golgi. As a result of the disrupted activity of the ATP7A protein, copper is poorly distributed to cells in the body. Copper accumulates in some tissues, such as the small intestine and kidneys, while the brain and other tissues have unusually low levels. The decreased supply of copper can reduce the activity of numerous copper-containing enzymes that are necessary for the structure and function of bone, skin, hair, blood vessels, and the nervous system.
^Larin D, Mekios C, Das K, Ross B, Yang AS, Gilliam TC (October 1999). "Characterization of the interaction between the Wilson and Menkes disease proteins and the cytoplasmic copper chaperone, HAH1p". J. Biol. Chem.274 (40): 28497–504. doi:10.1074/jbc.274.40.28497. PMID10497213.
^Lim CM, Cater MA, Mercer JF, La Fontaine S (September 2006). "Copper-dependent interaction of glutaredoxin with the N termini of the copper-ATPases (ATP7A and ATP7B) defective in Menkes and Wilson diseases". Biochem. Biophys. Res. Commun.348 (2): 428–36. doi:10.1016/j.bbrc.2006.07.067. PMID16884690.
Barnes N, Tsivkovskii R, Tsivkovskaia N, Lutsenko S (2005). "The copper-transporting ATPases, menkes and wilson disease proteins, have distinct roles in adult and developing cerebellum". J Biol Chem280 (10): 9640–5. doi:10.1074/jbc.M413840200. PMID15634671.
Greenough M, Pase L, Voskoboinik I, Petris MJ, O'Brien AW, Camakaris J (2004). "Signals regulating trafficking of Menkes (MNK; ATP7A) copper-translocating P-type ATPase in polarized MDCK cells". Am J Physiol Cell Physiol287 (5): C1463–71. doi:10.1152/ajpcell.00179.2004. PMID15269005.
Voskoboinik I, Camakaris J (2003). "Menkes copper-translocating P-type ATPase (ATP7A): biochemical and cell biology properties, and role in Menkes disease.". J. Bioenerg. Biomembr.34 (5): 363–71. doi:10.1023/A:1021250003104. PMID12539963.
La Fontaine S, Mercer JF (2007). "Trafficking of the copper-ATPases, ATP7A and ATP7B: role in copper homeostasis.". Arch. Biochem. Biophys.463 (2): 149–67. doi:10.1016/j.abb.2007.04.021. PMID17531189.
Dierick HA, Ambrosini L, Spencer J, Glover TW, Mercer JF (1996). "Molecular structure of the Menkes disease gene (ATP7A).". Genomics28 (3): 462–9. doi:10.1006/geno.1995.1175. PMID7490081.
Tümer Z, Vural B, Tønnesen T, Chelly J, Monaco AP, Horn N (1995). "Characterization of the exon structure of the Menkes disease gene using vectorette PCR.". Genomics26 (3): 437–42. doi:10.1016/0888-7543(95)80160-N. PMID7607665.
Kaler SG, Gallo LK, Proud VK, Percy AK, Mark Y, Segal NA et al. (1995). "Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus.". Nat. Genet.8 (2): 195–202. doi:10.1038/ng1094-195. PMID7842019.
Chelly J, Tümer Z, Tønnesen T, Petterson A, Ishikawa-Brush Y, Tommerup N et al. (1993). "Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein.". Nat. Genet.3 (1): 14–9. doi:10.1038/ng0193-14. PMID8490646.
Mercer JF, Livingston J, Hall B, Paynter JA, Begy C, Chandrasekharappa S et al. (1993). "Isolation of a partial candidate gene for Menkes disease by positional cloning.". Nat. Genet.3 (1): 20–5. doi:10.1038/ng0193-20. PMID8490647.
Vulpe C, Levinson B, Whitney S, Packman S, Gitschier J (1993). "Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase.". Nat. Genet.3 (1): 7–13. doi:10.1038/ng0193-7. PMID8490659.
Levinson B, Conant R, Schnur R, Das S, Packman S, Gitschier J (1997). "A repeated element in the regulatory region of the MNK gene and its deletion in a patient with occipital horn syndrome.". Hum. Mol. Genet.5 (11): 1737–42. doi:10.1093/hmg/5.11.1737. PMID8923001.
Dierick HA, Adam AN, Escara-Wilke JF, Glover TW (1997). "Immunocytochemical localization of the Menkes copper transport protein (ATP7A) to the trans-Golgi network.". Hum. Mol. Genet.6 (3): 409–16. doi:10.1093/hmg/6.3.409. PMID9147644.
Gitschier J, Moffat B, Reilly D, Wood WI, Fairbrother WJ (1998). "Solution structure of the fourth metal-binding domain from the Menkes copper-transporting ATPase.". Nat. Struct. Biol.5 (1): 47–54. doi:10.1038/nsb0198-47. PMID9437429.
Siggs OM, Cruite JT, Du X, Rutschmann S, Masliah E, Beutler B et al. (6 August 2012). "Disruption of copper homeostasis due to a mutation of Atp7a delays the onset of prion disease". Proceedings of the National Academy of Sciences109 (34): 13733–13738. doi:10.1073/pnas.1211499109. PMID22869751.