| Structural highlights
Disease
[ATP7A_HUMAN] Defects in ATP7A are the cause of Menkes disease (MNKD) [MIM:309400]; also known as kinky hair disease. MNKD is an X-linked recessive disorder of copper metabolism characterized by generalized copper deficiency. MNKD results in progressive neurodegeneration and connective-tissue disturbances: focal cerebral and cerebellar degeneration, early growth retardation, peculiar hair, hypopigmentation, cutis laxa, vascular complications and death in early childhood. The clinical features result from the dysfunction of several copper-dependent enzymes.[1] [2] [3] [4] [5] [6] [7] [8] [9] Defects in ATP7A are the cause of occipital horn syndrome (OHS) [MIM:304150]; also known as X-linked cutis laxa. OHS is an X-linked recessive disorder of copper metabolism. Common features are unusual facial appearance, skeletal abnormalities, chronic diarrhea and genitourinary defects. The skeletal abnormalities included occipital horns, short, broad clavicles, deformed radii, ulnae and humeri, narrowing of the rib cage, undercalcified long bones with thin cortical walls and coxa valga.[10] [11] Defects in ATP7A are a cause of distal spinal muscular atrophy X-linked type 3 (DSMAX3) [MIM:300489]. DSMAX3 is a neuromuscular disorder. Distal spinal muscular atrophy, also known as distal hereditary motor neuronopathy, represents a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs.[12]
Function
[ATP7A_HUMAN] May supply copper to copper-requiring proteins within the secretory pathway, when localized in the trans-Golgi network. Under conditions of elevated extracellular copper, it relocalized to the plasma membrane where it functions in the efflux of copper from cells.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Menkes disease is a fatal disease that can be induced by various mutations in the ATP7A gene, leading to unpaired uptake of dietary copper. The ATP7A gene encodes a copper(I)-translocating ATPase. Here the disease-causing A629P mutation, which occurs in the last of the six copper(I)-binding soluble domains of the ATPase (hereafter MNK6), was investigated. To understand why this apparently minor amino acid replacement is pathogenic, the solution structures and dynamics on various time-scales of wild-type and A629P-MNK6 were determined both in the apo- and copper(I)-loaded forms. The interaction in vitro with the physiological ATP7A copper(I)-donor (HAH1) was additionally studied. The A629P mutation makes the protein beta-sheet more solvent accessible, possibly resulting in an enhanced susceptibility of ATP7A to proteolytic cleavage and/or in reduced capability of copper(I)-translocation. A small reduction of the affinity for copper(I) is also observed. Both effects could concur to pathogenicity.
An atomic-level investigation of the disease-causing A629P mutant of the Menkes protein, ATP7A.,Banci L, Bertini I, Cantini F, Migliardi M, Rosato A, Wang S J Mol Biol. 2005 Sep 16;352(2):409-17. PMID:16083905[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Tumer Z, Moller LB, Horn N. Mutation spectrum of ATP7A, the gene defective in Menkes disease. Adv Exp Med Biol. 1999;448:83-95. PMID:10079817
- ↑ Das S, Levinson B, Whitney S, Vulpe C, Packman S, Gitschier J. Diverse mutations in patients with Menkes disease often lead to exon skipping. Am J Hum Genet. 1994 Nov;55(5):883-9. PMID:7977350
- ↑ Tumer Z, Lund C, Tolshave J, Vural B, Tonnesen T, Horn N. Identification of point mutations in 41 unrelated patients affected with Menkes disease. Am J Hum Genet. 1997 Jan;60(1):63-71. PMID:8981948
- ↑ Ambrosini L, Mercer JF. Defective copper-induced trafficking and localization of the Menkes protein in patients with mild and copper-treated classical Menkes disease. Hum Mol Genet. 1999 Aug;8(8):1547-55. PMID:10401004
- ↑ Ogawa A, Yamamoto S, Takayanagi M, Kogo T, Kanazawa M, Kohno Y. Identification of three novel mutations in the MNK gene in three unrelated Japanese patients with classical Menkes disease. J Hum Genet. 1999;44(3):206-9. PMID:10319589 doi:10.1007/s100380050144
- ↑ Gu YH, Kodama H, Murata Y, Mochizuki D, Yanagawa Y, Ushijima H, Shiba T, Lee CC. ATP7A gene mutations in 16 patients with Menkes disease and a patient with occipital horn syndrome. Am J Med Genet. 2001 Mar 15;99(3):217-22. PMID:11241493
- ↑ Hahn S, Cho K, Ryu K, Kim J, Pai K, Kim M, Park H, Yoo O. Identification of four novel mutations in classical Menkes disease and successful prenatal DNA diagnosis. Mol Genet Metab. 2001 May;73(1):86-90. PMID:11350187 doi:10.1006/mgme.2001.3169
- ↑ Moller LB, Bukrinsky JT, Molgaard A, Paulsen M, Lund C, Tumer Z, Larsen S, Horn N. Identification and analysis of 21 novel disease-causing amino acid substitutions in the conserved part of ATP7A. Hum Mutat. 2005 Aug;26(2):84-93. PMID:15981243 doi:10.1002/humu.20190
- ↑ Leon-Garcia G, Santana A, Villegas-Sepulveda N, Perez-Gonzalez C, Henrriquez-Esquiroz JM, de Leon-Garcia C, Wong C, Baeza I. The T1048I mutation in ATP7A gene causes an unusual Menkes disease presentation. BMC Pediatr. 2012 Sep 19;12:150. doi: 10.1186/1471-2431-12-150. PMID:22992316 doi:10.1186/1471-2431-12-150
- ↑ Ronce N, Moizard MP, Robb L, Toutain A, Villard L, Moraine C. A C2055T transition in exon 8 of the ATP7A gene is associated with exon skipping in an occipital horn syndrome family. Am J Hum Genet. 1997 Jul;61(1):233-8. PMID:9246006 doi:10.1016/S0002-9297(07)64297-9
- ↑ Tang J, Robertson S, Lem KE, Godwin SC, Kaler SG. Functional copper transport explains neurologic sparing in occipital horn syndrome. Genet Med. 2006 Nov;8(11):711-8. PMID:17108763 doi:10.109701.gim.0000245578.94312.1e
- ↑ Kennerson ML, Nicholson GA, Kaler SG, Kowalski B, Mercer JF, Tang J, Llanos RM, Chu S, Takata RI, Speck-Martins CE, Baets J, Almeida-Souza L, Fischer D, Timmerman V, Taylor PE, Scherer SS, Ferguson TA, Bird TD, De Jonghe P, Feely SM, Shy ME, Garbern JY. Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy. Am J Hum Genet. 2010 Mar 12;86(3):343-52. doi: 10.1016/j.ajhg.2010.01.027. Epub, 2010 Feb 18. PMID:20170900 doi:10.1016/j.ajhg.2010.01.027
- ↑ Banci L, Bertini I, Cantini F, Migliardi M, Rosato A, Wang S. An atomic-level investigation of the disease-causing A629P mutant of the Menkes protein, ATP7A. J Mol Biol. 2005 Sep 16;352(2):409-17. PMID:16083905 doi:10.1016/j.jmb.2005.07.034
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