RBCC

Full text data of ATP7A

ATP7A (MC1, MNK) [Confidence: high (present in two of the MS resources)]
Copper-transporting ATPase 1; 3.6.3.54 (Copper pump 1; Menkes disease-associated protein)

hRBCD IPI00028610
IPI00028610 Splice isoform 4 of Q04656 Copper-transporting ATPase 1 Splice isoform 4 of Q04656 Copper-transporting ATPase 1 membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 3 1 1 1 1 n/a n/a 1 n/a n/a Golgi, relocalizes to plasma membrane in presence of high Cu conc. splice isoforms 1, 2 and 5 found at its expected molecular weight found at molecular weight

Comments
Isoform Q04656-5 was detected.

UniProt Q04656
ID ATP7A_HUMAN Reviewed; 1500 AA.
AC Q04656; B1AT72; O00227; O00745; Q9BYY8;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 10-FEB-2009, sequence version 3.
DT 22-JAN-2014, entry version 168.
DE RecName: Full=Copper-transporting ATPase 1;
DE EC=3.6.3.54;
DE AltName: Full=Copper pump 1;
DE AltName: Full=Menkes disease-associated protein;
GN Name=ATP7A; Synonyms=MC1, MNK;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4), AND VARIANT THR-669.
RC TISSUE=Fibroblast;
RX PubMed=8490659; DOI=10.1038/ng0193-7;
RA Vulpe C.D., Levinson B., Whitney S., Packman S., Gitschier J.;
RT "Isolation of a candidate gene for Menkes disease and evidence that it
RT encodes a copper-transporting ATPase.";
RL Nat. Genet. 3:7-13(1993).
RN [2]
RP ERRATUM.
RA Vulpe C.D., Levinson B., Whitney S., Packman S., Gitschier J.;
RL Nat. Genet. 3:273-273(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 4), AND VARIANT THR-669.
RX PubMed=7607665; DOI=10.1016/0888-7543(95)80160-N;
RA Tuemer Z., Vural B., Toennesen T., Chelly J., Monaco A.P., Horn N.;
RT "Characterization of the exon structure of the Menkes disease gene
RT using vectorette PCR.";
RL Genomics 26:437-442(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RC TISSUE=Fibroblast;
RX PubMed=9693104;
RA Reddy M.C., Harris E.D.;
RT "Multiple transcripts coding for the menkes gene: evidence for
RT alternative splicing of Menkes mRNA.";
RL Biochem. J. 334:71-77(1998).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3).
RC TISSUE=Colon carcinoma, and Fibroblast;
RX PubMed=10079814;
RA Harris E.D., Reddy M.C., Qian Y., Tiffany-Castiglioni E., Majumdar S.,
RA Nelson J.;
RT "Multiple forms of the Menkes Cu-ATPase.";
RL Adv. Exp. Med. Biol. 448:39-51(1999).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-1447 (ISOFORM 4).
RX PubMed=7490081; DOI=10.1006/geno.1995.1175;
RA Dierick H.A., Ambrosini L., Spencer J., Glover T.W., Mercer J.F.B.;
RT "Molecular structure of the Menkes disease gene (ATP7A).";
RL Genomics 28:462-469(1995).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-626 (ISOFORM 4).
RC TISSUE=Kidney;
RX PubMed=8490646; DOI=10.1038/ng0193-14;
RA Chelly J., Tuemer Z., Toennesen T., Petterson A., Ishikawa-Brush Y.,
RA Tommerup N., Horn N., Monaco A.P.;
RT "Isolation of a candidate gene for Menkes disease that encodes a
RT potential heavy metal binding protein.";
RL Nat. Genet. 3:14-19(1993).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 12-529 (ISOFORM 4).
RC TISSUE=Endothelial cell;
RX PubMed=8490647; DOI=10.1038/ng0193-20;
RA Mercer J.F.B., Livingston J., Hall B., Paynter J.A., Begy C.,
RA Chandrasekharappa S., Lockhart P., Grimes A., Bhave M., Siemieniak D.,
RA Glover T.W.;
RT "Isolation of a partial candidate gene for Menkes disease by
RT positional cloning.";
RL Nat. Genet. 3:20-25(1993).
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 213-437.
RX PubMed=11214319; DOI=10.1038/35054550;
RA Murphy W.J., Eizirik E., Johnson W.E., Zhang Y.-P., Ryder O.A.,
RA O'Brien S.J.;
RT "Molecular phylogenetics and the origins of placental mammals.";
RL Nature 409:614-618(2001).
RN [12]
RP ALTERNATIVE SPLICING (ISOFORM 5), AND SUBCELLULAR LOCATION.
RX PubMed=9467005; DOI=10.1093/hmg/7.3.465;
RA Qi M., Byers P.H.;
RT "Constitutive skipping of alternatively spliced exon 10 in the ATP7A
RT gene abolishes Golgi localization of the menkes protein and produces
RT the occipital horn syndrome.";
RL Hum. Mol. Genet. 7:465-469(1998).
RN [13]
RP ALTERNATIVE SPLICING (ISOFORM 6).
RC TISSUE=Neuroblastoma;
RX PubMed=10970802; DOI=10.1042/0264-6021:3500855;
RA Reddy M.C., Majumdar S., Harris E.D.;
RT "Evidence for a Menkes-like protein with a nuclear targeting
RT sequence.";
RL Biochem. J. 350:855-863(2000).
RN [14]
RP SUBCELLULAR LOCATION.
RX PubMed=9147644; DOI=10.1093/hmg/6.3.409;
RA Dierick H.A., Adam A.N., Escara-Wilke J.F., Glover T.W.;
RT "Immunocytochemical localization of the Menkes copper transport
RT protein (ATP7A) to the trans-Golgi network.";
RL Hum. Mol. Genet. 6:409-416(1997).
RN [15]
RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF LEUCINE RESIDUES.
RX PubMed=10484781; DOI=10.1093/hmg/8.11.2107;
RA Petris M.J., Mercer J.F.B.;
RT "The Menkes protein (ATP7A; MNK) cycles via the plasma membrane both
RT in basal and elevated extracellular copper using a C-terminal di-
RT leucine endocytic signal.";
RL Hum. Mol. Genet. 8:2107-2115(1999).
RN [16]
RP INTERACTION WITH PDZD11.
RX PubMed=16051599; DOI=10.1074/jbc.M505889200;
RA Stephenson S.E., Dubach D., Lim C.M., Mercer J.F., La Fontaine S.;
RT "A single PDZ domain protein interacts with the Menkes copper ATPase,
RT ATP7A. A new protein implicated in copper homeostasis.";
RL J. Biol. Chem. 280:33270-33279(2005).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-339, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [19]
RP STRUCTURE BY NMR OF 375-446.
RX PubMed=9437429; DOI=10.1038/nsb0198-47;
RA Gitschier J., Moffat B., Reilly D., Wood W.I., Fairbrother W.J.;
RT "Solution structure of the fourth metal-binding domain from the Menkes
RT copper-transporting ATPase.";
RL Nat. Struct. Biol. 5:47-54(1998).
RN [20]
RP REVIEW, AND VARIANTS MNKD.
RX PubMed=10079817;
RA Tuemer Z., Moeller L.B., Horn N.;
RT "Mutation spectrum of ATP7A, the gene defective in Menkes disease.";
RL Adv. Exp. Med. Biol. 448:83-95(1999).
RN [21]
RP VARIANT LEU-767, AND VARIANT MNKD ARG-1302.
RX PubMed=7977350;
RA Das S., Levinson B., Whitney S., Vulpe C., Packman S., Gitschier J.;
RT "Diverse mutations in patients with Menkes disease often lead to exon
RT skipping.";
RL Am. J. Hum. Genet. 55:883-889(1994).
RN [22]
RP VARIANTS MNKD PRO-629; ARG-727; PRO-1006 AND ASP-1019.
RX PubMed=8981948;
RA Tuemer Z., Lund C., Tolshave J., Vural B., Toennesen T., Horn N.;
RT "Identification of point mutations in 41 unrelated patients affected
RT with Menkes disease.";
RL Am. J. Hum. Genet. 60:63-71(1997).
RN [23]
RP VARIANT OHS LEU-637.
RX PubMed=9246006;
RA Ronce N., Moizard M.P., Robb L., Toutain A., Villard L., Moraine C.;
RT "A C2055T transition in exon 8 of the ATP7A gene is associated with
RT exon skipping in an occipital horn syndrome family.";
RL Am. J. Hum. Genet. 61:233-238(1997).
RN [24]
RP VARIANT MNKD VAL-1362.
RX PubMed=10401004; DOI=10.1093/hmg/8.8.1547;
RA Ambrosini L., Mercer J.F.B.;
RT "Defective copper-induced trafficking and localization of the Menkes
RT protein in patients with mild and copper-treated classical Menkes
RT disease.";
RL Hum. Mol. Genet. 8:1547-1555(1999).
RN [25]
RP VARIANT MNKD ARG-873.
RX PubMed=10319589; DOI=10.1007/s100380050144;
RA Ogawa A., Yamamoto S., Takayanagi M., Kogo T., Kanazawa M., Kohno Y.;
RT "Identification of three novel mutations in the MNK gene in three
RT unrelated Japanese patients with classical Menkes disease.";
RL J. Hum. Genet. 44:206-209(1999).
RN [26]
RP INVOLVEMENT IN OCCIPITAL HORN SYNDROME.
RX PubMed=11431706; DOI=10.1086/321290;
RA Dagenais S.L., Adam A.N., Innis J.W., Glover T.W.;
RT "A novel frameshift mutation in exon 23 of ATP7A (MNK) results in
RT occipital horn syndrome and not in Menkes disease.";
RL Am. J. Hum. Genet. 69:420-427(2001).
RN [27]
RP VARIANTS MNKD ARG-1344 AND PHE-1345.
RX PubMed=11241493;
RX DOI=10.1002/1096-8628(2001)9999:9999<::AID-AJMG1167>3.0.CO;2-R;
RA Gu Y.-H., Kodama H., Murata Y., Mochizuki D., Yanagawa Y.,
RA Ushijima H., Shiba T., Lee C.-C.;
RT "ATP7A gene mutations in 16 patients with Menkes disease and a patient
RT with occipital horn syndrome.";
RL Am. J. Med. Genet. 99:217-222(2001).
RN [28]
RP VARIANTS MNKD ARG-706; ASP-1118 AND ARG-1255.
RX PubMed=11350187; DOI=10.1006/mgme.2001.3169;
RA Hahn S., Cho K., Ryu K., Kim J., Pai K., Kim M., Park H., Yoo O.;
RT "Identification of four novel mutations in classical Menkes disease
RT and successful prenatal DNA diagnosis.";
RL Mol. Genet. Metab. 73:86-90(2001).
RN [29]
RP VARIANTS MNKD HIS-844; ARG-853; VAL-860; ARG-876; GLU-876; ARG-924;
RP ARG-1000; VAL-1007; ASP-1015; GLY-1044; PRO-1100; GLU-1282; GLU-1300;
RP VAL-1302; LYS-1304; ALA-1305; ARG-1315; VAL-1325; ARG-1369 AND
RP PHE-1397.
RX PubMed=15981243; DOI=10.1002/humu.20190;
RA Moeller L.B., Bukrinsky J.T., Moelgaard A., Paulsen M., Lund C.,
RA Tuemer Z., Larsen S., Horn N.;
RT "Identification and analysis of 21 novel disease-causing amino acid
RT substitutions in the conserved part of ATP7A.";
RL Hum. Mutat. 26:84-93(2005).
RN [30]
RP VARIANT OHS SER-1304, AND CHARACTERIZATION OF VARIANT OHS SER-1304.
RX PubMed=17108763; DOI=10.1097/01.gim.0000245578.94312.1e;
RA Tang J., Robertson S., Lem K.E., Godwin S.C., Kaler S.G.;
RT "Functional copper transport explains neurologic sparing in occipital
RT horn syndrome.";
RL Genet. Med. 8:711-718(2006).
RN [31]
RP VARIANTS DSMAX3 ILE-994 AND SER-1386, AND CHARACTERIZATION OF VARIANTS
RP DSMAX3 ILE-994 AND SER-1386.
RX PubMed=20170900; DOI=10.1016/j.ajhg.2010.01.027;
RA Kennerson M.L., Nicholson G.A., Kaler S.G., Kowalski B.,
RA Mercer J.F.B., Tang J., Llanos R.M., Chu S., Takata R.I.,
RA Speck-Martins C.E., Baets J., Almeida-Souza L., Fischer D.,
RA Timmerman V., Taylor P.E., Scherer S.S., Ferguson T.A., Bird T.D.,
RA De Jonghe P., Feely S.M.E., Shy M.E., Garbern J.Y.;
RT "Missense mutations in the copper transporter gene ATP7A cause X-
RT linked distal hereditary motor neuropathy.";
RL Am. J. Hum. Genet. 86:343-352(2010).
RN [32]
RP VARIANT MNKD ILE-1048.
RX PubMed=22992316; DOI=10.1186/1471-2431-12-150;
RA De Leon-Garcia G., Santana A., Villegas-Sepulveda N.,
RA Perez-Gonzalez C., Henrriquez-Esquiroz J.M., De Leon-Garcia C.,
RA Wong C., Baeza I.;
RT "The T1048I mutation in ATP7A gene causes an unusual Menkes disease
RT presentation.";
RL BMC Pediatr. 12:150-150(2012).
CC -!- FUNCTION: May supply copper to copper-requiring proteins within
CC the secretory pathway, when localized in the trans-Golgi network.
CC Under conditions of elevated extracellular copper, it relocalized
CC to the plasma membrane where it functions in the efflux of copper
CC from cells.
CC -!- CATALYTIC ACTIVITY: ATP + H(2)O + Cu(+)(Side 1) = ADP + phosphate
CC + Cu(+)(Side 2).
CC -!- SUBUNIT: Monomer. Interacts with PDZD11.
CC -!- INTERACTION:
CC Q5EBL8:PDZD11; NbExp=4; IntAct=EBI-7706409, EBI-1644207;
CC -!- SUBCELLULAR LOCATION: Golgi apparatus, trans-Golgi network
CC membrane; Multi-pass membrane protein. Cell membrane; Multi-pass
CC membrane protein. Note=Cycles constitutively between the trans-
CC Golgi network (TGN) and the plasma membrane. Predominantly found
CC in the TGN and relocalized to the plasma membrane in response to
CC elevated copper levels.
CC -!- SUBCELLULAR LOCATION: Isoform 3: Cytoplasm, cytosol (Probable).
CC -!- SUBCELLULAR LOCATION: Isoform 5: Endoplasmic reticulum.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=4;
CC IsoId=Q04656-1; Sequence=Displayed;
CC Name=1;
CC IsoId=Q04656-2; Sequence=VSP_000419;
CC Name=2;
CC IsoId=Q04656-3; Sequence=VSP_000420;
CC Name=3; Synonyms=2-16;
CC IsoId=Q04656-4; Sequence=VSP_000424;
CC Note=Lacks 6 transmembrane regions and 5 heavy-metal-associated
CC (HMA) domains;
CC Name=5;
CC IsoId=Q04656-5; Sequence=VSP_000425;
CC Note=Lacks the transmembrane domains 3 and 4. Expressed at a low
CC level in several tissues of normal individuals and is the only
CC isoform found in patients with OHS;
CC Name=6; Synonyms=NML45;
CC IsoId=Q04656-6; Sequence=VSP_000421, VSP_000422, VSP_000423;
CC Note=Lacks all transmembrane regions and 5
CC heavy-metal-associated (HMA) domains, but has a putative nuclear
CC localization signal attached at the N-terminus;
CC -!- TISSUE SPECIFICITY: Found in most tissues except liver. Isoform 3
CC is widely expressed including in liver cell lines. Isoform 1 is
CC expressed in fibroblasts, choriocarcinoma, colon carcinoma and
CC neuroblastoma cell lines. Isoform 2 is expressed in fibroblasts,
CC colon carcinoma and neuroblastoma cell lines.
CC -!- DOMAIN: The C-terminal di-leucine, 1487-Leu-Leu-1488, is an
CC endocytic targeting signal which functions in retrieving recycling
CC from the plasma membrane to the TGN. Mutation of the di-leucine
CC signal results in the accumulation of the protein in the plasma
CC membrane.
CC -!- DISEASE: Menkes disease (MNKD) [MIM:309400]: An X-linked recessive
CC disorder of copper metabolism characterized by generalized copper
CC deficiency. MNKD results in progressive neurodegeneration and
CC connective-tissue disturbances: focal cerebral and cerebellar
CC degeneration, early growth retardation, peculiar hair,
CC hypopigmentation, cutis laxa, vascular complications and death in
CC early childhood. The clinical features result from the dysfunction
CC of several copper-dependent enzymes. A mild form of the disease
CC has been described, in which cerebellar ataxia and moderate
CC developmental delay predominate. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Occipital horn syndrome (OHS) [MIM:304150]: An X-linked
CC recessive disorder of copper metabolism. Common features are
CC unusual facial appearance, skeletal abnormalities, chronic
CC diarrhea and genitourinary defects. The skeletal abnormalities
CC include occipital horns, short, broad clavicles, deformed radii,
CC ulnae and humeri, narrowing of the rib cage, undercalcified long
CC bones with thin cortical walls and coxa valga. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Distal spinal muscular atrophy, X-linked, 3 (DSMAX3)
CC [MIM:300489]: A neuromuscular disorder. Distal spinal muscular
CC atrophy, also known as distal hereditary motor neuronopathy,
CC represents a heterogeneous group of neuromuscular disorders caused
CC by selective degeneration of motor neurons in the anterior horn of
CC the spinal cord, without sensory deficit in the posterior horn.
CC The overall clinical picture consists of a classical distal
CC muscular atrophy syndrome in the legs without clinical sensory
CC loss. The disease starts with weakness and wasting of distal
CC muscles of the anterior tibial and peroneal compartments of the
CC legs. Later on, weakness and atrophy may expand to the proximal
CC muscles of the lower limbs and/or to the distal upper limbs.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the cation transport ATPase (P-type)
CC (TC 3.A.3) family. Type IB subfamily.
CC -!- SIMILARITY: Contains 6 HMA domains.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ATP7A";
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Heavy metal - Issue 79
CC of February 2007;
CC URL="http://web.expasy.org/spotlight/back_issues/sptlt079.shtml";
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DR EMBL; L06133; AAA35580.1; -; mRNA.
DR EMBL; X82336; CAB94714.1; -; Genomic_DNA.
DR EMBL; X82337; CAB94714.1; JOINED; Genomic_DNA.
DR EMBL; X82338; CAB94714.1; JOINED; Genomic_DNA.
DR EMBL; X82339; CAB94714.1; JOINED; Genomic_DNA.
DR EMBL; X82340; CAB94714.1; JOINED; Genomic_DNA.
DR EMBL; X82341; CAB94714.1; JOINED; Genomic_DNA.
DR EMBL; X82342; CAB94714.1; JOINED; Genomic_DNA.
DR EMBL; X82343; CAB94714.1; JOINED; Genomic_DNA.
DR EMBL; X82344; CAB94714.1; JOINED; Genomic_DNA.
DR EMBL; X82345; CAB94714.1; JOINED; Genomic_DNA.
DR EMBL; X82346; CAB94714.1; JOINED; Genomic_DNA.
DR EMBL; X82347; CAB94714.1; JOINED; Genomic_DNA.
DR EMBL; X82348; CAB94714.1; JOINED; Genomic_DNA.
DR EMBL; X82349; CAB94714.1; JOINED; Genomic_DNA.
DR EMBL; X82350; CAB94714.1; JOINED; Genomic_DNA.
DR EMBL; X82351; CAB94714.1; JOINED; Genomic_DNA.
DR EMBL; X82352; CAB94714.1; JOINED; Genomic_DNA.
DR EMBL; X82353; CAB94714.1; JOINED; Genomic_DNA.
DR EMBL; X82354; CAB94714.1; JOINED; Genomic_DNA.
DR EMBL; X82355; CAB94714.1; JOINED; Genomic_DNA.
DR EMBL; X82356; CAB94714.1; JOINED; Genomic_DNA.
DR EMBL; AL645821; CAI42806.1; -; Genomic_DNA.
DR EMBL; CH471104; EAW98605.1; -; Genomic_DNA.
DR EMBL; U27381; AAA96010.1; -; Genomic_DNA.
DR EMBL; U27361; AAA96010.1; JOINED; Genomic_DNA.
DR EMBL; U27362; AAA96010.1; JOINED; Genomic_DNA.
DR EMBL; U27363; AAA96010.1; JOINED; Genomic_DNA.
DR EMBL; U27365; AAA96010.1; JOINED; Genomic_DNA.
DR EMBL; U27366; AAA96010.1; JOINED; Genomic_DNA.
DR EMBL; U27367; AAA96010.1; JOINED; Genomic_DNA.
DR EMBL; U27368; AAA96010.1; JOINED; Genomic_DNA.
DR EMBL; U27369; AAA96010.1; JOINED; Genomic_DNA.
DR EMBL; U27370; AAA96010.1; JOINED; Genomic_DNA.
DR EMBL; U27371; AAA96010.1; JOINED; Genomic_DNA.
DR EMBL; U27372; AAA96010.1; JOINED; Genomic_DNA.
DR EMBL; U27373; AAA96010.1; JOINED; Genomic_DNA.
DR EMBL; U27374; AAA96010.1; JOINED; Genomic_DNA.
DR EMBL; U27375; AAA96010.1; JOINED; Genomic_DNA.
DR EMBL; U27376; AAA96010.1; JOINED; Genomic_DNA.
DR EMBL; U27377; AAA96010.1; JOINED; Genomic_DNA.
DR EMBL; U27378; AAA96010.1; JOINED; Genomic_DNA.
DR EMBL; U27379; AAA96010.1; JOINED; Genomic_DNA.
DR EMBL; U27380; AAA96010.1; JOINED; Genomic_DNA.
DR EMBL; X69208; CAA49145.1; -; mRNA.
DR EMBL; L06476; AAA16974.1; -; mRNA.
DR EMBL; Z94801; CAB08162.2; -; Genomic_DNA.
DR EMBL; Z94753; CAB08160.1; -; Genomic_DNA.
DR EMBL; AY011418; AAG47452.1; -; Genomic_DNA.
DR PIR; S36149; S36149.
DR RefSeq; NP_000043.4; NM_000052.6.
DR RefSeq; NP_001269153.1; NM_001282224.1.
DR RefSeq; XP_005262204.1; XM_005262147.1.
DR UniGene; Hs.496414; -.
DR UniGene; Hs.733232; -.
DR PDB; 1AW0; NMR; -; A=375-446.
DR PDB; 1KVI; NMR; -; A=1-79.
DR PDB; 1KVJ; NMR; -; A=1-79.
DR PDB; 1Q8L; NMR; -; A=164-246.
DR PDB; 1S6O; NMR; -; A=169-240.
DR PDB; 1S6U; NMR; -; A=169-240.
DR PDB; 1Y3J; NMR; -; A=486-558.
DR PDB; 1Y3K; NMR; -; A=486-558.
DR PDB; 1YJR; NMR; -; A=562-633.
DR PDB; 1YJT; NMR; -; A=562-633.
DR PDB; 1YJU; NMR; -; A=562-633.
DR PDB; 1YJV; NMR; -; A=562-633.
DR PDB; 2AW0; NMR; -; A=375-446.
DR PDB; 2G9O; NMR; -; A=275-352.
DR PDB; 2GA7; NMR; -; A=275-352.
DR PDB; 2K1R; NMR; -; A=5-77.
DR PDB; 2KIJ; NMR; -; A=806-924.
DR PDB; 2KMV; NMR; -; A=1051-1231.
DR PDB; 2KMX; NMR; -; A=1051-1231.
DR PDB; 3CJK; X-ray; 1.80 A; B=7-77.
DR PDBsum; 1AW0; -.
DR PDBsum; 1KVI; -.
DR PDBsum; 1KVJ; -.
DR PDBsum; 1Q8L; -.
DR PDBsum; 1S6O; -.
DR PDBsum; 1S6U; -.
DR PDBsum; 1Y3J; -.
DR PDBsum; 1Y3K; -.
DR PDBsum; 1YJR; -.
DR PDBsum; 1YJT; -.
DR PDBsum; 1YJU; -.
DR PDBsum; 1YJV; -.
DR PDBsum; 2AW0; -.
DR PDBsum; 2G9O; -.
DR PDBsum; 2GA7; -.
DR PDBsum; 2K1R; -.
DR PDBsum; 2KIJ; -.
DR PDBsum; 2KMV; -.
DR PDBsum; 2KMX; -.
DR PDBsum; 3CJK; -.
DR DisProt; DP00282; -.
DR ProteinModelPortal; Q04656; -.
DR SMR; Q04656; 1-633, 713-1413.
DR IntAct; Q04656; 1.
DR MINT; MINT-106053; -.
DR STRING; 9606.ENSP00000345728; -.
DR TCDB; 3.A.3.5.6; the p-type atpase (p-atpase) superfamily.
DR PhosphoSite; Q04656; -.
DR DMDM; 223590241; -.
DR PaxDb; Q04656; -.
DR PRIDE; Q04656; -.
DR DNASU; 538; -.
DR Ensembl; ENST00000341514; ENSP00000345728; ENSG00000165240.
DR Ensembl; ENST00000343533; ENSP00000343026; ENSG00000165240.
DR Ensembl; ENST00000350425; ENSP00000343678; ENSG00000165240.
DR GeneID; 538; -.
DR KEGG; hsa:538; -.
DR UCSC; uc004ecx.4; human.
DR CTD; 538; -.
DR GeneCards; GC0XP077166; -.
DR HGNC; HGNC:869; ATP7A.
DR HPA; HPA012887; -.
DR MIM; 300011; gene.
DR MIM; 300489; phenotype.
DR MIM; 304150; phenotype.
DR MIM; 309400; phenotype.
DR neXtProt; NX_Q04656; -.
DR Orphanet; 565; Menkes disease.
DR Orphanet; 198; Occipital horn syndrome.
DR Orphanet; 139557; X-linked distal spinal muscular atrophy.
DR PharmGKB; PA72; -.
DR eggNOG; COG2217; -.
DR HOGENOM; HOG000250397; -.
DR HOVERGEN; HBG050616; -.
DR KO; K17686; -.
DR OMA; CASNIEN; -.
DR OrthoDB; EOG7C2R0G; -.
DR BRENDA; 3.6.3.4; 2681.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR ChiTaRS; ATP7A; human.
DR EvolutionaryTrace; Q04656; -.
DR GeneWiki; ATP7A; -.
DR GenomeRNAi; 538; -.
DR NextBio; 2231; -.
DR PRO; PR:Q04656; -.
DR Bgee; Q04656; -.
DR CleanEx; HS_ATP7A; -.
DR Genevestigator; Q04656; -.
DR GO; GO:0016323; C:basolateral plasma membrane; IDA:UniProtKB.
DR GO; GO:0031526; C:brush border membrane; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005770; C:late endosome; IDA:UniProtKB.
DR GO; GO:0043005; C:neuron projection; ISS:UniProtKB.
DR GO; GO:0043025; C:neuronal cell body; ISS:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0030141; C:secretory granule; IEA:Ensembl.
DR GO; GO:0005802; C:trans-Golgi network; IDA:UniProtKB.
DR GO; GO:0030140; C:trans-Golgi network transport vesicle; IMP:HGNC.
DR GO; GO:0005524; F:ATP binding; TAS:HGNC.
DR GO; GO:0004008; F:copper-exporting ATPase activity; ISS:UniProtKB.
DR GO; GO:0016532; F:superoxide dismutase copper chaperone activity; ISS:UniProtKB.
DR GO; GO:0001568; P:blood vessel development; ISS:UniProtKB.
DR GO; GO:0001974; P:blood vessel remodeling; ISS:UniProtKB.
DR GO; GO:0051216; P:cartilage development; ISS:UniProtKB.
DR GO; GO:0006878; P:cellular copper ion homeostasis; IMP:UniProtKB.
DR GO; GO:0021702; P:cerebellar Purkinje cell differentiation; ISS:UniProtKB.
DR GO; GO:0030199; P:collagen fibril organization; ISS:UniProtKB.
DR GO; GO:0015677; P:copper ion import; ISS:UniProtKB.
DR GO; GO:0048813; P:dendrite morphogenesis; IEA:Ensembl.
DR GO; GO:0010273; P:detoxification of copper ion; ISS:UniProtKB.
DR GO; GO:0042417; P:dopamine metabolic process; ISS:UniProtKB.
DR GO; GO:0048251; P:elastic fiber assembly; ISS:UniProtKB.
DR GO; GO:0051542; P:elastin biosynthetic process; ISS:UniProtKB.
DR GO; GO:0042414; P:epinephrine metabolic process; ISS:UniProtKB.
DR GO; GO:0031069; P:hair follicle morphogenesis; ISS:UniProtKB.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0007626; P:locomotory behavior; ISS:UniProtKB.
DR GO; GO:0048286; P:lung alveolus development; ISS:UniProtKB.
DR GO; GO:0007005; P:mitochondrion organization; ISS:UniProtKB.
DR GO; GO:0048553; P:negative regulation of metalloenzyme activity; ISS:UniProtKB.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0048812; P:neuron projection morphogenesis; ISS:UniProtKB.
DR GO; GO:0042421; P:norepinephrine biosynthetic process; IEA:Ensembl.
DR GO; GO:0042415; P:norepinephrine metabolic process; ISS:UniProtKB.
DR GO; GO:0018205; P:peptidyl-lysine modification; ISS:UniProtKB.
DR GO; GO:0043473; P:pigmentation; ISS:UniProtKB.
DR GO; GO:0048554; P:positive regulation of metalloenzyme activity; ISS:UniProtKB.
DR GO; GO:0051353; P:positive regulation of oxidoreductase activity; IDA:UniProtKB.
DR GO; GO:0021860; P:pyramidal neuron development; ISS:UniProtKB.
DR GO; GO:0010468; P:regulation of gene expression; IEA:Ensembl.
DR GO; GO:0002082; P:regulation of oxidative phosphorylation; ISS:UniProtKB.
DR GO; GO:0001836; P:release of cytochrome c from mitochondria; IEA:Ensembl.
DR GO; GO:0019430; P:removal of superoxide radicals; ISS:UniProtKB.
DR GO; GO:0010041; P:response to iron(III) ion; IEA:Ensembl.
DR GO; GO:0010043; P:response to zinc ion; IEA:Ensembl.
DR GO; GO:0042428; P:serotonin metabolic process; ISS:UniProtKB.
DR GO; GO:0042093; P:T-helper cell differentiation; ISS:UniProtKB.
DR GO; GO:0006568; P:tryptophan metabolic process; ISS:UniProtKB.
DR GO; GO:0006570; P:tyrosine metabolic process; IEA:Ensembl.
DR Gene3D; 2.70.150.10; -; 1.
DR Gene3D; 3.40.1110.10; -; 2.
DR Gene3D; 3.40.50.1000; -; 2.
DR InterPro; IPR023299; ATPase_P-typ_cyto_domN.
DR InterPro; IPR018303; ATPase_P-typ_P_site.
DR InterPro; IPR008250; ATPase_P-typ_transduc_dom_A.
DR InterPro; IPR027256; Cation_transp_P-typ_ATPase_IB.
DR InterPro; IPR001757; Cation_transp_P_typ_ATPase.
DR InterPro; IPR023214; HAD-like_dom.
DR InterPro; IPR017969; Heavy-metal-associated_CS.
DR InterPro; IPR006121; HeavyMe-assoc_HMA.
DR InterPro; IPR006122; HMA_Cu_ion-bd.
DR Pfam; PF00122; E1-E2_ATPase; 1.
DR Pfam; PF00403; HMA; 6.
DR Pfam; PF00702; Hydrolase; 1.
DR PRINTS; PR00119; CATATPASE.
DR SUPFAM; SSF55008; SSF55008; 6.
DR SUPFAM; SSF56784; SSF56784; 2.
DR SUPFAM; SSF81660; SSF81660; 2.
DR TIGRFAMs; TIGR01525; ATPase-IB_hvy; 1.
DR TIGRFAMs; TIGR01494; ATPase_P-type; 2.
DR TIGRFAMs; TIGR00003; TIGR00003; 6.
DR PROSITE; PS00154; ATPASE_E1_E2; 1.
DR PROSITE; PS01047; HMA_1; 6.
DR PROSITE; PS50846; HMA_2; 6.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Cell membrane;
KW Complete proteome; Copper; Copper transport; Cytoplasm;
KW Disease mutation; Endoplasmic reticulum; Glycoprotein;
KW Golgi apparatus; Hydrolase; Ion transport; Magnesium; Membrane;
KW Metal-binding; Neurodegeneration; Nucleotide-binding; Phosphoprotein;
KW Polymorphism; Reference proteome; Repeat; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1 1500 Copper-transporting ATPase 1.
FT /FTId=PRO_0000046311.
FT TOPO_DOM 1 653 Cytoplasmic (Potential).
FT TRANSMEM 654 675 Helical; (Potential).
FT TOPO_DOM 676 714 Extracellular (Potential).
FT TRANSMEM 715 734 Helical; (Potential).
FT TOPO_DOM 735 741 Cytoplasmic (Potential).
FT TRANSMEM 742 762 Helical; (Potential).
FT TOPO_DOM 763 781 Extracellular (Potential).
FT TRANSMEM 782 802 Helical; (Potential).
FT TOPO_DOM 803 936 Cytoplasmic (Potential).
FT TRANSMEM 937 959 Helical; (Potential).
FT TOPO_DOM 960 989 Extracellular (Potential).
FT TRANSMEM 990 1011 Helical; (Potential).
FT TOPO_DOM 1012 1356 Cytoplasmic (Potential).
FT TRANSMEM 1357 1374 Helical; (Potential).
FT TOPO_DOM 1375 1385 Extracellular (Potential).
FT TRANSMEM 1386 1405 Helical; (Potential).
FT TOPO_DOM 1406 1500 Cytoplasmic (Potential).
FT DOMAIN 9 75 HMA 1.
FT DOMAIN 172 238 HMA 2.
FT DOMAIN 278 344 HMA 3.
FT DOMAIN 378 444 HMA 4.
FT DOMAIN 489 555 HMA 5.
FT DOMAIN 565 631 HMA 6.
FT REGION 1486 1500 PDZD11-binding.
FT MOTIF 1487 1488 Endocytosis signal.
FT COMPBIAS 355 362 Poly-Ser.
FT ACT_SITE 1044 1044 4-aspartylphosphate intermediate (By
FT similarity).
FT METAL 1301 1301 Magnesium (By similarity).
FT METAL 1305 1305 Magnesium (By similarity).
FT MOD_RES 339 339 Phosphoserine.
FT MOD_RES 357 357 Phosphoserine (By similarity).
FT MOD_RES 1212 1212 Phosphothreonine (By similarity).
FT MOD_RES 1466 1466 Phosphoserine (By similarity).
FT CARBOHYD 686 686 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 975 975 N-linked (GlcNAc...) (Potential).
FT VAR_SEQ 1 1 M -> MRKLSIRKRDNNLLK (in isoform 1).
FT /FTId=VSP_000419.
FT VAR_SEQ 1 1 M -> MRKLSIRKRDNNLLKPSSASSLGIAVSLGRPVLSRS
FT SSGTVNLLEEVGLHIRDTAFSSTKLLEAISTVSAQVEELAV
FT HNECY (in isoform 2).
FT /FTId=VSP_000420.
FT VAR_SEQ 1 1 M -> MRKLSIRKRDNNLLKECNEEIK (in isoform
FT 6).
FT /FTId=VSP_000421.
FT VAR_SEQ 42 1038 Missing (in isoform 3).
FT /FTId=VSP_000424.
FT VAR_SEQ 53 81 DPKLQTPKTLQEAIDDMGFDAVIHNPDPL -> AHWFGFAA
FT LDGICSNGCFICFCSTFFSSL (in isoform 6).
FT /FTId=VSP_000422.
FT VAR_SEQ 82 1499 Missing (in isoform 6).
FT /FTId=VSP_000423.
FT VAR_SEQ 725 802 Missing (in isoform 5).
FT /FTId=VSP_000425.
FT VARIANT 629 629 A -> P (in MNKD).
FT /FTId=VAR_000699.
FT VARIANT 637 637 S -> L (in OHS; dbSNP:rs28936068).
FT /FTId=VAR_009999.
FT VARIANT 669 669 I -> T (in dbSNP:rs2234935).
FT /FTId=VAR_016119.
FT VARIANT 703 703 R -> H (in dbSNP:rs2234936).
FT /FTId=VAR_016120.
FT VARIANT 706 706 L -> R (in MNKD).
FT /FTId=VAR_023261.
FT VARIANT 727 727 G -> R (in MNKD).
FT /FTId=VAR_000700.
FT VARIANT 767 767 V -> L (in dbSNP:rs2227291).
FT /FTId=VAR_010000.
FT VARIANT 844 844 R -> H (in MNKD).
FT /FTId=VAR_023262.
FT VARIANT 853 853 G -> R (in MNKD).
FT /FTId=VAR_023263.
FT VARIANT 860 860 G -> V (in MNKD).
FT /FTId=VAR_023264.
FT VARIANT 873 873 L -> R (in MNKD).
FT /FTId=VAR_010001.
FT VARIANT 876 876 G -> E (in MNKD).
FT /FTId=VAR_010002.
FT VARIANT 876 876 G -> R (in MNKD).
FT /FTId=VAR_023265.
FT VARIANT 924 924 Q -> R (in MNKD).
FT /FTId=VAR_023266.
FT VARIANT 994 994 T -> I (in DSMAX3; demonstrates impaired
FT intracellular trafficking compared to
FT control with some of the mutant protein
FT remaining in the Golgi apparatus after
FT exposure to copper).
FT /FTId=VAR_063882.
FT VARIANT 1000 1000 C -> R (in MNKD).
FT /FTId=VAR_010003.
FT VARIANT 1006 1006 L -> P (in MNKD).
FT /FTId=VAR_000701.
FT VARIANT 1007 1007 A -> V (in MNKD).
FT /FTId=VAR_023267.
FT VARIANT 1015 1015 G -> D (in MNKD).
FT /FTId=VAR_023268.
FT VARIANT 1019 1019 G -> D (in MNKD).
FT /FTId=VAR_000702.
FT VARIANT 1044 1044 D -> G (in MNKD).
FT /FTId=VAR_023269.
FT VARIANT 1048 1048 T -> I (in MNKD).
FT /FTId=VAR_068831.
FT VARIANT 1100 1100 L -> P (in MNKD).
FT /FTId=VAR_023270.
FT VARIANT 1118 1118 G -> D (in MNKD).
FT /FTId=VAR_023271.
FT VARIANT 1255 1255 G -> R (in MNKD).
FT /FTId=VAR_023272.
FT VARIANT 1282 1282 K -> E (in MNKD).
FT /FTId=VAR_023273.
FT VARIANT 1300 1300 G -> E (in MNKD).
FT /FTId=VAR_010004.
FT VARIANT 1302 1302 G -> R (in MNKD).
FT /FTId=VAR_010005.
FT VARIANT 1302 1302 G -> V (in MNKD).
FT /FTId=VAR_010006.
FT VARIANT 1304 1304 N -> K (in MNKD).
FT /FTId=VAR_023274.
FT VARIANT 1304 1304 N -> S (in OHS; has approximately 33%
FT residual copper transport).
FT /FTId=VAR_063883.
FT VARIANT 1305 1305 D -> A (in MNKD).
FT /FTId=VAR_010007.
FT VARIANT 1315 1315 G -> R (in MNKD).
FT /FTId=VAR_023275.
FT VARIANT 1325 1325 A -> V (in MNKD).
FT /FTId=VAR_023276.
FT VARIANT 1344 1344 S -> R (in MNKD).
FT /FTId=VAR_023277.
FT VARIANT 1345 1345 I -> F (in MNKD).
FT /FTId=VAR_023278.
FT VARIANT 1362 1362 A -> V (in MNKD).
FT /FTId=VAR_010008.
FT VARIANT 1369 1369 G -> R (in MNKD).
FT /FTId=VAR_023279.
FT VARIANT 1386 1386 P -> S (in DSMAX3; demonstrates impaired
FT intracellular trafficking compared to
FT control with some mutant protein
FT remaining in the Golgi apparatus after
FT exposure to copper).
FT /FTId=VAR_063884.
FT VARIANT 1397 1397 S -> F (in MNKD).
FT /FTId=VAR_023280.
FT VARIANT 1464 1464 I -> V (in dbSNP:rs2234938).
FT /FTId=VAR_016121.
FT MUTAGEN 1487 1488 LL->AA: Loss of relocalization to the
FT trans-Golgi.
FT CONFLICT 10 10 V -> A (in Ref. 4; no nucleotide entry).
FT CONFLICT 36 36 V -> E (in Ref. 10; AAA16974).
FT CONFLICT 336 336 E -> V (in Ref. 1; AAA35580 and 8;
FT AAA96010).
FT CONFLICT 446 446 D -> G (in Ref. 6; CAB08162).
FT CONFLICT 624 624 S -> G (in Ref. 6; CAB08162).
FT CONFLICT 725 725 F -> V (in Ref. 6; CAB08162).
FT CONFLICT 833 833 S -> R (in Ref. 6; CAB08162).
FT CONFLICT 1099 1099 E -> K (in Ref. 4; no nucleotide entry).
FT CONFLICT 1171 1171 N -> S (in Ref. 6; CAB08162).
FT CONFLICT 1178 1178 Y -> C (in Ref. 4; no nucleotide entry).
FT CONFLICT 1178 1178 Y -> H (in Ref. 1; AAA35580, 3; CAB94714
FT and 8; AAA96010).
FT CONFLICT 1220 1220 D -> G (in Ref. 6; CAB08162).
FT CONFLICT 1295 1295 R -> W (in Ref. 4; no nucleotide entry).
FT CONFLICT 1313 1313 N -> D (in Ref. 4; no nucleotide entry).
FT CONFLICT 1336 1336 N -> D (in Ref. 6; CAB08162).
FT CONFLICT 1350 1350 E -> K (in Ref. 1; AAA35580, 3; CAB94714
FT and 8; AAA96010).
FT CONFLICT 1376 1376 V -> M (in Ref. 6; CAB08162).
FT CONFLICT 1396 1396 S -> P (in Ref. 4; no nucleotide entry).
FT CONFLICT 1409 1409 L -> R (in Ref. 6; CAB08160).
FT CONFLICT 1455 1455 R -> W (in Ref. 4; no nucleotide entry).
FT TURN 4 6
FT STRAND 8 14
FT HELIX 20 31
FT STRAND 33 35
FT STRAND 36 42
FT TURN 43 46
FT STRAND 47 52
FT TURN 54 56
FT HELIX 59 68
FT STRAND 73 77
FT STRAND 165 169
FT STRAND 171 177
FT TURN 180 182
FT HELIX 187 194
FT STRAND 199 204
FT TURN 207 209
FT STRAND 210 215
FT TURN 217 219
FT HELIX 222 231
FT STRAND 236 238
FT TURN 242 244
FT STRAND 277 285
FT HELIX 288 299
FT STRAND 305 311
FT TURN 312 315
FT STRAND 316 321
FT STRAND 324 326
FT HELIX 329 336
FT TURN 340 342
FT STRAND 344 346
FT STRAND 377 384
FT HELIX 388 400
FT STRAND 408 411
FT TURN 412 415
FT STRAND 416 421
FT TURN 423 425
FT HELIX 428 438
FT STRAND 441 446
FT STRAND 488 495
FT HELIX 497 499
FT HELIX 502 510
FT STRAND 513 518
FT TURN 523 526
FT STRAND 527 532
FT TURN 534 536
FT HELIX 539 549
FT STRAND 553 557
FT STRAND 566 571
FT TURN 575 577
FT HELIX 578 586
FT STRAND 592 598
FT TURN 599 602
FT STRAND 603 608
FT TURN 610 613
FT HELIX 614 626
FT STRAND 628 633
FT HELIX 808 814
FT STRAND 818 824
FT STRAND 826 828
FT STRAND 833 838
FT TURN 839 841
FT STRAND 847 849
FT STRAND 860 862
FT STRAND 868 870
FT TURN 872 875
FT STRAND 887 889
FT STRAND 894 898
FT STRAND 901 904
FT TURN 908 910
FT HELIX 912 919
FT TURN 920 923
FT STRAND 1055 1061
FT TURN 1065 1067
FT HELIX 1070 1079
FT HELIX 1080 1082
FT STRAND 1083 1085
FT HELIX 1087 1100
FT STRAND 1112 1114
FT TURN 1115 1117
FT STRAND 1118 1123
FT HELIX 1127 1129
FT TURN 1135 1139
FT TURN 1150 1153
FT STRAND 1161 1166
FT TURN 1167 1171
FT HELIX 1172 1174
FT STRAND 1178 1183
FT HELIX 1185 1191
FT HELIX 1197 1208
FT STRAND 1212 1218
FT STRAND 1221 1229
SQ SEQUENCE 1500 AA; 163374 MW; CF8FF9EA061D463B CRC64;
MDPSMGVNSV TISVEGMTCN SCVWTIEQQI GKVNGVHHIK VSLEEKNATI IYDPKLQTPK
TLQEAIDDMG FDAVIHNPDP LPVLTDTLFL TVTASLTLPW DHIQSTLLKT KGVTDIKIYP
QKRTVAVTII PSIVNANQIK ELVPELSLDT GTLEKKSGAC EDHSMAQAGE VVLKMKVEGM
TCHSCTSTIE GKIGKLQGVQ RIKVSLDNQE ATIVYQPHLI SVEEMKKQIE AMGFPAFVKK
QPKYLKLGAI DVERLKNTPV KSSEGSQQRS PSYTNDSTAT FIIDGMHCKS CVSNIESTLS
ALQYVSSIVV SLENRSAIVK YNASSVTPES LRKAIEAVSP GLYRVSITSE VESTSNSPSS
SSLQKIPLNV VSQPLTQETV INIDGMTCNS CVQSIEGVIS KKPGVKSIRV SLANSNGTVE
YDPLLTSPET LRGAIEDMGF DATLSDTNEP LVVIAQPSSE MPLLTSTNEF YTKGMTPVQD
KEEGKNSSKC YIQVTGMTCA SCVANIERNL RREEGIYSIL VALMAGKAEV RYNPAVIQPP
MIAEFIRELG FGATVIENAD EGDGVLELVV RGMTCASCVH KIESSLTKHR GILYCSVALA
TNKAHIKYDP EIIGPRDIIH TIESLGFEAS LVKKDRSASH LDHKREIRQW RRSFLVSLFF
CIPVMGLMIY MMVMDHHFAT LHHNQNMSKE EMINLHSSMF LERQILPGLS VMNLLSFLLC
VPVQFFGGWY FYIQAYKALK HKTANMDVLI VLATTIAFAY SLIILLVAMY ERAKVNPITF
FDTPPMLFVF IALGRWLEHI AKGKTSEALA KLISLQATEA TIVTLDSDNI LLSEEQVDVE
LVQRGDIIKV VPGGKFPVDG RVIEGHSMVD ESLITGEAMP VAKKPGSTVI AGSINQNGSL
LICATHVGAD TTLSQIVKLV EEAQTSKAPI QQFADKLSGY FVPFIVFVSI ATLLVWIVIG
FLNFEIVETY FPGYNRSISR TETIIRFAFQ ASITVLCIAC PCSLGLATPT AVMVGTGVGA
QNGILIKGGE PLEMAHKVKV VVFDKTGTIT HGTPVVNQVK VLTESNRISH HKILAIVGTA
ESNSEHPLGT AITKYCKQEL DTETLGTCID FQVVPGCGIS CKVTNIEGLL HKNNWNIEDN
NIKNASLVQI DASNEQSSTS SSMIIDAQIS NALNAQQYKV LIGNREWMIR NGLVINNDVN
DFMTEHERKG RTAVLVAVDD ELCGLIAIAD TVKPEAELAI HILKSMGLEV VLMTGDNSKT
ARSIASQVGI TKVFAEVLPS HKVAKVKQLQ EEGKRVAMVG DGINDSPALA MANVGIAIGT
GTDVAIEAAD VVLIRNDLLD VVASIDLSRE TVKRIRINFV FALIYNLVGI PIAAGVFMPI
GLVLQPWMGS AAMAASSVSV VLSSLFLKLY RKPTYESYEL PARSQIGQKS PSEISVHVGI
DDTSRNSPKL GLLDRIVNYS RASINSLLSD KRSLNSVVTS EPDKHSLLVG DFREDDDTAL
//

MIM 300011
*RECORD*
*FIELD* NO
300011
*FIELD* TI
*300011 ATPase, Cu(2+)-TRANSPORTING, ALPHA POLYPEPTIDE; ATP7A
*FIELD* TX

DESCRIPTION
read more
The ATP7A gene encodes a transmembrane copper-transporting P-type ATPase
(summary by Vulpe et al., 1993).

CLONING

The ATP7A gene was cloned as a candidate for the site of mutations
causing Menkes disease (MNK; 309400) by 3 independent groups (Vulpe et
al., 1993; Chelly et al., 1993; Mercer et al., 1993). By a database
search of the predicted sequence, Vulpe et al. (1993) found strong
homology to P-type ATPases, a family of integral membrane proteins that
use an aspartylphosphate intermediate to transport cations across
membranes. The 1,500-residue protein was found to have the
characteristics of a copper-binding protein. It has 6 N-terminal copper
binding sites and a catalytic transduction core with several functional
domains. Northern blot analysis showed that the mRNA of the gene, which
was symbolized 'MNK' before its precise nature was known, is present in
a variety of cell types and tissues, except liver, in which expression
is reduced or absent. The findings were consistent with the clinical
observation that the liver is largely unaffected in Menkes disease and
fails to accumulate excess copper.

Levinson et al. (1994) and Mercer et al. (1994) isolated the mouse
homolog of the Menkes disease gene. The mouse protein shows 89% identity
to the human protein, and both proteins contain 8 transmembrane domains.

GENE STRUCTURE

Tumer et al. (1995) determined that the ATP7A gene spans about 150 kb of
genomic DNA and contains 23 exons. The ATG start codon is in the second
exon. The ATP7A and ATP7B (606882) genes showed strikingly similar
exonic structures, with almost identical structures starting from the
fifth metal-binding domain, suggesting the presence of a common ancestor
encoding 1, and possibly 2, metal-binding domains in addition to the
ATPase 'core.'

Dierick et al. (1995) showed that the ATP7A gene contains 23 exons
distributed over approximately 140 kb of genomic DNA. The authors showed
that exon 10 is alternatively spliced. They found that the structures of
the ATP7A and ATP7B genes are similar in the 3-prime two-thirds region,
consistent with their common evolutionary ancestry.

GENE FUNCTION

Kuo et al. (1997) determined the gene expression patterns during mouse
embryonic development for the Atp7a and Atp7b genes by RNA in situ
hybridization. Atp7a expression was widespread throughout development
whereas Atp7b expression was more delimited. Kuo et al. (1997) suggested
that Atp7a functions primarily in the homeostatic maintenance of cell
copper levels, whereas Atp7b may be involved specifically in the
biosynthesis of distinct cuproproteins in different tissues.

Studies in cultured cells localized the MNK protein to the final
compartment of the Golgi apparatus, the trans-Golgi network (TGN). At
this location, MNK is predicted to supply copper to the copper-dependent
enzymes as they migrate through the secretory pathway. However, under
conditions of elevated extracellular copper, the MNK protein undergoes a
rapid relocalization to the plasma membrane where it functions in the
efflux of copper from cells. By in vitro mutagenesis of the human ATP7A
cDNA and immunofluorescence detection of mutant forms of the MNK protein
expressed in cultured cells, Petris et al. (1998) demonstrated that the
dileucine, L1487L1488, was essential for localization of MNK within the
TGN, but not for copper efflux. They suggested that this dileucine motif
is a putative endocytic targeting motif necessary for the retrieval of
MNK from the plasma membrane to the TGN. Qian et al. (1998) and Francis
et al. (1998) demonstrated that the third transmembrane region of the
MNK protein functions as a TGN targeting signal; Petris et al. (1998)
suggested that MNK localization to the TGN may be a 2-step process
involving TGN retention by the transmembrane region, and recycling to
this compartment from the plasma membrane via the L1487L1488 motif.

Petris et al. (2000) investigated whether the ATP7A protein is required
for the activity of tyrosinase (606933), a copper-dependent enzyme
involved in melanogenesis that is synthesized within the secretory
pathway. Recombinant tyrosinase expressed in immortalized Menkes
fibroblast cell lines was inactive, whereas in normal fibroblasts known
to express ATP7A there was substantial tyrosinase activity. Coexpression
of ATP7A and tyrosinase from plasmid constructs in Menkes fibroblasts
led to the activation of tyrosinase and melanogenesis. This
ATP7A-dependent activation of tyrosinase was impaired by the chelation
of copper in the medium of cells and after mutation of the invariant
phosphorylation site at aspartic acid residue 1044 of ATP7A. The authors
proposed that ATP7A transports copper into the secretory pathway of
mammalian cells to activate copper-dependent enzymes.

Cobbold et al. (2002) showed that endogenous ATP7A in cultured cell
lines was localized to the distal Golgi apparatus and translocated to
the plasma membrane in response to exogenous copper ions. This transport
event was not blocked by expression of a dominant-negative mutant
protein kinase D (PRKCM; 605435), an enzyme implicated in regulating
constitutive trafficking from the TGN to the plasma membrane, whereas
constitutive transport of CD4 (186940) was inhibited. In contrast,
protein kinase A inhibitors blocked copper-stimulated ATP7A delivery to
the plasma membrane. Expression of constitutively active Rho GTPases
such as CDC42 (116952), RAC1 (602048), and RhoA (ARHA; 165390) revealed
a requirement for CDC42 in the trafficking of ATP7A to the cell surface.
Furthermore, overexpression of WASP (300392) inhibited anterograde
transport of ATP7A, further supporting regulation by the CDC42 GTPase.

Cobbold et al. (2003) showed that ATP7A is internalized by a novel
pathway that is independent of clathrin (see 118960)-mediated
endocytosis. Expression of dominant-negative mutants of the dynamin-1
(DNM1; 602377), dynamin-2 (DNM2; 602378), and EPS15 (600051) proteins
that block clathrin-dependent endocytosis of the transferrin receptor
did not inhibit internalization of endogenous ATP7A or an ATP7A reporter
molecule (CD8-MCF1). Similarly, inhibitors of caveolae (see
601047)-mediated uptake did not affect ATP7A internalization and
prevented uptake of BODIPY-ganglioside GM1, a caveolae marker. In
contrast, expression of a constitutively active mutant of the RAC1
GTPase inhibited plasma membrane internalization of both the ATP7A and
transferrin receptor transmembrane proteins. Cobbold et al. (2003)
concluded that their findings defined a novel route required for ATP7A
internalization and delivery to endosomes.

Schlief et al. (2006) stated that ATP7A is required for production of an
NMDA receptor (see GRIN1; 138249)-dependent releasable copper pool
within hippocampal neurons, suggesting a role for copper in
activity-dependent modulation of synaptic activity. In support of this
hypothesis, they found that copper chelation exacerbated NMDA-mediated
excitotoxic cell death in rat primary hippocampal neurons, whereas
addition of copper was protective and significantly decreased
cytoplasmic calcium levels after NMDA receptor activation. The
protective effect of copper in hippocampal neurons depended on
endogenous nitric oxide production, demonstrating an in vivo link
between neuroprotection, copper metabolism, and nitrosylation. Using
'brindled' mice, a model of Menkes disease (see ANIMAL MODEL), Schlief
et al. (2006) showed that ATP7A was required for these copper-dependent
effects. Hippocampal neurons isolated from newborn brindled mice showed
marked sensitivity to endogenous glutamate-mediated NMDA
receptor-dependent excitotoxicity in vitro, and mild hypoxic/ischemic
insult to these mice in vivo resulted in significantly increased
caspase-3 (CASP3; 600636) activation and neuronal injury.

Setty et al. (2008) showed that the pigment cell-specific cuproenzyme
tyrosinase acquires copper only transiently and inefficiently within the
trans-Golgi network of mouse melanocytes. To catalyze melanin synthesis,
tyrosinase is subsequently reloaded with copper within specialized
organelles called melanosomes. Copper is supplied to melanosomes by
ATP7A, a cohort of which localizes to melanosomes in a BLOC1 (biogenesis
of lysosome-related organelles complex-1)-dependent manner. Setty et al.
(2008) concluded that cell type-specific localization of a metal
transporter is required to sustain metallation of an endomembrane
cuproenzyme, providing a mechanism for exquisite spatial control of
metalloenzyme activity. Moreover, because BLOC1 subunits are mutated in
subtypes of the genetic disease Hermansky-Pudlak syndrome (203300),
these results also show that defects in copper transporter localization
contribute to hypopigmentation, and hence perhaps other synaptic
defects, in Hermansky-Pudlak syndrome.

BIOCHEMICAL FEATURES

- Crystal Structure

Gourdon et al. (2011) presented the structure of a P-type class IB (PIB)
ATPase, a Legionella pneumophila CopA copper ATPase, in a copper-free
form, as determined by x-ray crystallography at 3.2-angstrom resolution.
The structure indicates a 3-stage copper transport pathway involving
several conserved residues. A PIB-specific transmembrane helix kinks at
a double-glycine motif displaying an amphipathic helix that lines a
putative copper entry point at the intracellular interface. Comparisons
to calcium ATPase suggested an ATPase-coupled copper release mechanism
from the binding sites in the membrane via an extracellular exit site.
Gourdon et al. (2011) suggested that their structure will provide a
framework for analysis of missense mutations in human ATP7A and ATP7B
(606882) proteins associated with Menkes and Wilson disease (277900),
respectively.

MOLECULAR GENETICS

- Menkes Disease

Kaler et al. (1994) identified mutations in the ATP7A gene in affected
members of a family with Menkes disease (300011.0001).

Tumer et al. (1997) examined genomic DNA of 41 unrelated patients
affected with the classic severe form of Menkes disease. Using SSCP
analysis and direct sequencing of the exons amplified by PCR, they
identified a different mutation in each of the 41 patients, including 19
insertion/deletions, 10 nonsense mutations, 4 missense mutations, and 8
splice site alterations. Approximately 90% of the mutations were
predicted to result in truncation of the ATP7A protein. In 20 patients
the mutations were within exons 7-10, and half of these mutations
affected exon 8. Furthermore, 5 alterations were observed within the
6-bp sequence at the splice donor site of intron 8, which would be
predicted to affect the efficiency of exon 8 splicing. Tumer et al.
(1997) speculated that the region encoded by exon 8 may serve as a
'stalk,' joining its metal-binding domains and its ATPase core.

Poulsen et al. (2002) stated that approximately 15% of mutations causing
Menkes disease are partial gene deletions. Poulsen et al. (2002)
demonstrated that intragenic polymorphic markers can be used for carrier
detection as well as for the identification of affected males.

Moller et al. (2005) identified 21 novel missense mutations in the ATP7A
gene in patients with Menkes disease. The mutations were located within
the conserved part of ATP7A between residues val842 and ser1404.
Molecular 3-dimensional modeling based on the structure of ATP2A1
(108730) showed that the mutations were more spatially clustered than
expected from the primary sequence. The authors suggested that some of
the mutations may interfere with copper binding.

Moizard et al. (2011) identified pathogenic mutations in the ATP7A gene
in 34 (85%) of 40 patients referred for either Menkes disease (n = 38)
or OHS (n = 2). There were 23 point mutations, including 9 missense
mutations, 7 splice site variants, 4 nonsense mutations, and 3 small
insertions or deletions, as well as 7 intragenic deletions. Twenty-one
of the mutations were novel, indicating that most mutations are private.
In addition, there were 4 whole exon duplications, which expanded the
mutational spectrum in the ATP7A gene. Large rearrangements, either
deletions or duplications, accounted for 32.4% of the mutations. Most
(66.6%) of the point mutations resulted in impaired ATP7A transcript
splicing.

- Occipital Horn Syndrome

Kaler et al. (1994) identified mutations in the ATP7A gene in a patient
with X-linked cutis laxa, also known as occipital horn syndrome (OHS;
304150) (see 300011.0002).

Levinson et al. (1996) detected a small deletion in a region 5-prime to
the MNK gene in a patient with occipital horn syndrome. Whereas a normal
control had 3 tandem 98-bp repeats upstream of the transcription start
site, the patient had a deletion of 1 of the repeats. Although cell
lines from the patient showed no reduction in MNK mRNA, there was a
decrease in activity of a chloramphenicol acetyltransferase (CAT)
reporter gene, suggesting that the repeat sequences may regulate MNK
gene expression in the context of a larger region of genomic DNA.
Levinson et al. (1996) speculated that their studies of MNK mRNA levels
in the patient's cultured cells did not accurately reflect the in vivo
situation. The deletion was not identified in 110 control individuals.

- X-Linked Distal Spinal Muscular Atrophy 3

In affected members of 2 families with X-linked distal spinal muscular
atrophy-3 (SMAX3; 300489), previously reported by Takata et al. (2004)
and Kennerson et al. (2009), Kennerson et al. (2010) identified 2
different mutations in the ATP7A gene: T994I (300011.0015) and P1386S
(300011.0016), respectively. In vitro functional expression assays
indicated that the mutations resulted in impaired copper transport into
the secretory pathway for incorporation into nascent proproteins,
perhaps due to reduced conformational flexibility. Kennerson et al.
(2010) suggested that the late onset of distal muscular atrophy implies
that these mutations produced attenuated effects that required years to
provoke pathologic consequences. Motor neurons may be particularly
sensitive to perturbations in copper homeostasis or copper deficiency,
which may impair normal axonal growth and synaptogenesis.

GENOTYPE/PHENOTYPE CORRELATIONS

The clinical outcome of copper replacement therapy in Menkes disease in
the small number of cases reported has ranged from poor (Kaler et al.,
1995) to favorable (Christodoulou et al., 1998). Kim et al. (2003)
characterized the biochemical and cell biologic defect associated with
an MNK mutation (300011.0010) found in a successfully treated patient
(Kaler et al., 1996). The mutation involved the deletion of exon 8 of
the ATP7A gene, which encodes a small region between the sixth copper
binding site and the first membrane spanning domain of the MNK protein.
The mutant protein localized correctly to the TGN and was capable of
transporting copper to tyrosinase, a copper-dependent enzyme that is
synthesized within secretory compartments. However, in cells exposed to
increased copper, the MNK mutant protein failed to traffic to the plasma
membrane. This represented the first trafficking defective Menkes
disease mutation demonstrated to retain copper transport function,
thereby showing that trafficking and transport functions of MNK ATPase
can be uncoupled. Thus, certain Menkes disease mutations that inhibit
copper-induced trafficking of an otherwise functional copper transporter
may be particularly responsive to copper replacement therapy.

Moller et al. (2000) stated that more than 150 point mutations had been
identified in the ATP7A gene. Most of these mutations were found to lead
to the classic form of Menkes disease, and a few to the milder occipital
horn syndrome. They reported 2 Menkes patients and 1 OHS patient with
mutations in the splice donor site of intron 6. RT-PCR studies showed
that exon 6 was deleted in most ATP7A transcripts of all 3 patients, but
RT-PCR amplification with an exon 6-specific primer identified small
amounts of exon 6-containing mRNA products from all 3 patients. Direct
sequencing showed that only the patient with OHS had correctly spliced
exon 6-containing transcripts at levels of 2 to 5% of controls. These
findings indicated that the presence of barely detectable amounts of
correctly spliced ATP7A transcript is sufficient to permit the
development of the milder OHS phenotype, as opposed to classic Menkes
disease. The patient with OHS was found to have a mutation at a less
conserved position of the donor splice site (300011.0006) compared to 1
of the Menkes patients who had a mutation at a more conserved position
of the splice site (300011.0007).

Gu et al. (2001) searched for mutations in the ATP7A gene in 17
unrelated Japanese males with Menkes disease and 2 Japanese males with
occipital horn syndrome. In 16 of 17 males with Menkes disease, they
identified 16 mutations, including 4 deletions, 2 insertions, 6 nonsense
mutations, 2 missense mutations, and 2 splice site mutations. Of 2 males
with occipital horn syndrome, 1 had a splice site mutation in intron 6
that led to normal-size and smaller-size transcripts. The amount of the
normal-size transcripts in his cultured skin fibroblasts was 19% of the
normal level. Serum copper and ceruloplasmin levels were normal, whereas
his cultured skin fibroblasts contained increased levels of copper. This
patient, first seen at the age of 12 months, had developmental delay,
hypotonia, and cutis laxa. Bladder diverticula were detected at age 21
months, and occipital horns at age 6 years.

ANIMAL MODEL

The 'mottled' (Mo) mouse comprises several phenotypic variations
presumed to result from a single X-linked locus. Hemizygous 'pewter'
(pew) males have isolated coat color changes; 'blotchy' (blo) males have
connective tissue defects; 'brindled' (br) and 'macular' (ml) mice have
neurologic disease; and 'dappled' (dp) and 'tortoiseshell' (to) mice
have perinatal lethality. For a detailed description of the 'mottled'
mouse, a model for Menkes syndrome, see 309400. Levinson et al. (1994)
and Mercer et al. (1994) found that 2 variant forms of the mottled
mouse, dappled and blotchy, resulted from allelic mutations at the
mottled locus. The dappled mutant had no Atp7a mRNA, resulting from a
deletion or rearrangement of DNA in the Atp7a gene, and the blotchy
mouse mutant had abnormal mRNA expression, likely resulting from a
splice site mutation.

Reed and Boyd (1997) identified mutations in the Atp7a gene in the
'viable brindled' (vbr) and 'brindled' mottled mouse mutants. Cecchi et
al. (1997) identified mutations in mouse Atp7a that could explain the
mottled phenotype in 9 of 10 mutants analyzed. The authors commented
that the wide spectrum of mutations detected in the mouse Atp7a gene
provided an explanation for at least part of the wide phenotypic
variation observed in mottled mutant mice.

Grimes et al. (1997) showed that the 'brindled' mouse has a deletion of
2 amino acids in a highly conserved region of the Atp7a gene. They also
presented Western blot data for the normal gene product in tissues. In
the kidney, immunohistochemistry demonstrated the protein in proximal
and distal tubules, with a distribution identical in mutant and normal
mice. This distribution was considered consistent with the protein being
involved in copper resorption from the urine.

*FIELD* AV
.0001
MENKES DISEASE, MILD
ATP7A, IVSXDS, A-T, +3

Family A, studied by Kaler et al. (1994), had 4 males with a Menkes
disease (309400) phenotype featuring comparatively enhanced longevity
and milder neurodevelopmental deficits compared with classic Menkes
disease. All 4 affected males were still living at ages 36, 26, 16, and
2 years. The 3 oldest had onset of seizures at ages 4, 8, and 3 years of
age, respectively. All 4 had pili torti, bladder diverticula, and
striking skin laxity. The 3 oldest had occipital exostoses and chronic
diarrhea. In family A, the affected males were found to have a mutation
in a splice donor site leading to deletion of 118 nucleotides
constituting so-called exon X. An A-to-T transversion at the +3 position
resulted in 3 consecutive thymine bases in this splice donor site.
Because the mutation did not alter a restriction site in the gene, Kaler
et al. (1994) developed a PCR-based assay to screen members of the
family for the mutation, using the amplification refractory mutation
system (ARMS).

.0002
OCCIPITAL HORN SYNDROME
ATP7A, IVSAS, 2642A-G, -2

In a 15-year-old male whose clinical and radiographic abnormalities
corresponded closely to those compiled in 20 patients with occipital
horn syndrome (304150) by Tsukahara et al. (1994), Kaler et al. (1994)
identified a 2462A-G transition at the 3-prime end (position -2) of a
92-bp exon in the ATP7A gene, resulting in exon skipping and activation
of a cryptic splice acceptor site. Maintenance of some normal splicing
was demonstrable by RT-PCR, cDNA sequencing, and ribonuclease
protection.

.0003
OCCIPITAL HORN SYNDROME
ATP7A, SER637LEU

Ronce et al. (1997) observed a family in which 6 males in 5 sibships in
3 generations connected through carrier females who had occipital horn
syndrome (304150). Studies of the proband's DNA revealed a 2055C-T
transition in exon 8 of the ATP7A gene, resulting in a ser637-to-leu
(S637L) substitution. This transition was associated with both normal
processing of ATP7A mRNA and exon skipping, with 2 alternatively spliced
abnormal products: 1 with only exon 8 skipped and the other with 3
consecutive exons--8, 9, and 10--skipped. Ronce et al. (1997) noted that
exon 8, the site of this mutation, appears to be particularly vulnerable
to mutations, and referred to a nonsense mutation in the same codon,
S637X, that had been reported by Tumer et al. (1997). The fact that the
OHS phenotype but not the Menkes (309400) phenotype was observed in this
patient could be explained by the presence of the normally processed
mRNA and by the likely production of functional ATP7A protein.

The patient reported by Ronce et al. (1997) was suggested to have
Ehlers-Danlos syndrome within the first week of birth because of the
combination of long length, pectus excavatum, loose skin, and joint
laxity. Right and left inguinal hernias were observed from 4 months of
age and required repeated surgical interventions. Recurrent urinary
bacterial infections revealed bladder diverticula at 15 months of age.
Skin biopsies at 5 years of age revealed fragmented collagen fibers and
a relative excess of elastic fibers. Normally elevated radiocopper
retention was demonstrated in the patient's fibroblasts. At the age of
25 years, the man was tall (181.5 cm), with narrow shoulders, marked
pectus excavatum, and dorsal kyphosis, flat feet, loose wrists and
finger joints, a weak abdominal wall, soft pinnae, and loose and
hyperelastic skin. The hair was kinky, with numerous, although moderate,
pili torti. All of the teeth had gray enamel, and the inferior incisors
had particular spicules. Skeletal x-rays showed mild occipital
exostoses, thickening of muscle insertion zones on the long bones, and
irregular shapes of the cubitus and radius, with distortion of the
proximal end of the radius and enlargement of the distal end of the
tibia. The proband died suddenly at 27 years of age; autopsy showed
perforated gastric ulcer and peritonitis. His mother had a long face,
large pinnae, and loose skin, which could be interpreted as symptoms of
the carrier state.

.0004
OCCIPITAL HORN SYNDROME
ATP7A, 8-BP DEL, NT1552

In a Mexican-American male infant who presented as a neonate with severe
congenital cutis laxa (304150), Packman et al. (1997) identified an 8-bp
deletion (1552del8) in exon 5 of the ATP7A gene, which encodes the fifth
metal-binding domain. The out-of-frame deletion resulted in a downstream
premature stop codon. At birth, the child had extremely loose skin, with
truncal folds and sagging facial skin, hyperextensible joints, pectus
excavatum, craniotabes, and stridor. His hair was sparse and coarse,
with frontal balding. Significant neurologic abnormalities were first
noted at age 2 months, after which time he showed progressive neurologic
deterioration until death at age 13 months. MRI at age 2.5 weeks showed
tortuosity and looping of intracranial vessels. Skin biopsy at that time
showed fragmented elastin fibers. Serum copper was normal on day 1, but
low at age 4 months.

.0005
MENKES DISEASE
ATP7A, ARG980TER

In a patient with lethal neonatal Menkes disease (309400) reported by
Jankov et al. (1998), Horn (1999) identified a C-to-T transition in the
ATP7A gene, resulting in an arg980-to-ter (R980X) substitution. The
child presented as a newborn with acute onset of severe intraabdominal
bleeding, hemorrhagic shock, and multiple fractures leading to death at
day 27. Menkes disease was diagnosed at autopsy and confirmed by copper
accumulation studies on cultured fibroblasts. Such an early onset of
fatal complications in Menkes disease had not previously been reported.
The R980X mutation was said to have been identical to the mutation found
in an unrelated male with Menkes disease who died at the age of 4 years
without severe connective tissue disease (Horn, 1999).

.0006
OCCIPITAL HORN SYNDROME
ATP7A, IVS6DS, T-A, +6

In a 24-year-old man with a clinical picture typical of occipital horn
syndrome (304150), Moller et al. (2000) identified a T-to-A transversion
at the donor splice site of intron 6 of the ATP7A gene. Cell culture
studies showed levels of ATP7A transcripts at 2 to 5% of controls. The
patient had a narrow thorax, joint deformities, right inguinal hernia,
bladder diverticula, vascular abnormalities, and chronic diarrhea.
Occipital horns of about 5 cm had been found when he was 18. The
patient's skin was dry, loose, and hypopigmented, and his hair was
coarse. Complications included aneurysms of abdominal vessels, hepatic
artery, and splenic artery which were treated surgically. The patient
showed psychomotor retardation, with psychotic characteristics
(manic-depressive behavior). He was able to walk without support at age
3 years and started talking at age 3.5 years. Serum copper and
ceruloplasmin levels were significantly below normal.
Copper-incorporation studies showed abnormal accumulation and retention,
confirming that the patient suffered from a variant of Menkes disease. A
brother who had similar connective tissue abnormalities and coarse hair,
but was more severely retarded, had died at age 8 years (Mentzel et al.,
1999).

.0007
MENKES DISEASE
ATP7A, IVS6DS, G-A, +1

Moller et al. (2000) described a splice site mutation involving the +1
position of intron 6 of the ATP7A gene in a patient with classic Menkes
disease (309400). The patient had shown hypoglycemia and repeated
episodes of hypothermia during the neonatal period. At the age of 8
weeks, he was hospitalized because of feeding difficulties that were
accompanied by therapy-resistant seizures. At 10 weeks of age, his hair
started to fall out and was replaced by hair with an abnormal texture,
raising suspicion of Menkes disease. Serum copper and ceruloplasmin
levels were very low. Over the next months he developed subdural
hematomas, high arched palate, and wormian bones in the lambdoid suture
of the occipital region. Bladder diverticula were diagnosed at age 1.5
years. Copper histidine therapy was initiated when he was 8 months old
and continued until his death at age 21 years.

.0008
OCCIPITAL HORN SYNDROME
ATP7A, 1-BP DEL, 4497G

In affected members of a family with occipital horn syndrome (304150),
Dagenais et al. (2001) identified a 1-bp deletion (4497delG) in exon 23
of the ATP7A gene, resulting in a frameshift at codon 1451 and premature
termination of the protein. Although abundant levels of mutant
transcript were present, there were substantially reduced levels of the
truncated protein, which lacked the key dileucine motif L1487L1488. This
dileucine motif functions as an endocytic signal for ATP7A cycling
between the trans-Golgi network and the plasma membrane. Steady-state
localization of ATP7A to the trans-Golgi network is necessary for proper
activity of lysyl oxidase (153455), which is the predominant cuproenzyme
whose activity is deficient in OHS and which is essential for
maintenance of connective-tissue integrity. The proband in the family
reported by Dagenais et al. (2001) sat without assistance at the age of
7 months and was able to crawl at the age of 7.5 months. On examination,
he exhibited multiple bladder diverticula, renal calculus,
vesicoureteral reflux, bilateral inguinal hernia repair, neurogenic
bladder, genu valgum, and pectus excavatum. He also had mildly
hyperelastic skin, especially over the abdomen, and required special
education. Skeletal survey showed bilateral occipital horns, mild
lower-thoracic and lumbar platyspondyly, marked pectus excavatum, broad
scapular necks, clavicular handlebar/hammer contour, humeral and femoral
diaphyseal wavy contour, bilateral coxa valga, and minimal dextroconvex
scoliosis. He had an affected brother, a maternal uncle, and a cousin
with slight variability in severity.

.0009
MENKES DISEASE
ATP7A, GLY1019ASP

In transfected cultured cells, Kim et al. (2002) characterized a
gly1019-to-asp (G1019D) mutation, located in the large cytoplasmic loop
of the MNK protein, that causes Menkes disease (309400). In
copper-limiting conditions, the G1019D mutant protein was retained in
the endoplasmic reticulum. This mislocalization was corrected by the
addition of copper to cells via a process that was dependent upon the
copper-binding sites at the N-terminal region of the MNK protein.
Reduced growth temperature and the chemical chaperone glycerol corrected
the mislocalization of the G1019D mutant, suggesting that this mutation
interferes with protein folding in the secretory pathway. These findings
identified G1019D as the first conditional mutation associated with
Menkes disease and demonstrated correction of the mislocalized protein
by copper supplementation. The findings provided a molecular framework
for understanding how mutations that affect the proper folding of the
MNK transporter in Menkes patients may be responsive to parenteral
copper therapy.

.0010
MENKES DISEASE, COPPER-REPLACEMENT RESPONSIVE
ATP7A, EX8 DEL

Kaler et al. (1996) described successful early copper therapy in Menkes
disease (309400) associated with a mutant transcript containing a small
in-frame deletion. This splice site mutation resulted in deletion of
exon 8, which encodes a small region between the sixth copper binding
site and the first membrane-spanning domain of MNK protein. Kim et al.
(2003) demonstrated that the mutant protein was defective in
copper-induced trafficking but its copper transport mutant function was
retained. The sequence of exon 8 was deleted from the mutant protein
extended between serine-624 and glutamine-649 that was deleted in the
in-frame transcript of the patient and replaced by 624 ile-arg.

.0011
MENKES DISEASE
ATP7A, 8-BP DEL, NT408

In a child with classic Menkes disease (309400) and an unusual finding
of early occipital horns, Gerard-Blanluet et al. (2004) identified an
8-bp deletion (408delCAATCAGA) in the ATP7A gene, resulting in a
frameshift starting at amino acid 136, addition of 21 aberrant amino
acids, and loss of the 1,363 amino acids of the C-terminal sequence.
They presented hypotheses concerning the occurrence of the rare feature
of occipital horn.

.0012
MENKES DISEASE
ATP7A, EX3-4 DEL

Tumer et al. (2003) reported 2 patients with Menkes disease (309400)
with unexpectedly mild symptoms and long survival. The proband was 27
years old and his affected maternal cousin 24 years at the time of the
report. The proband showed developmental delay at age 6 months and at
age 2 years began having seizures. At age 4 years, he developed head
control, and, at age 9 years, his motor and mental status was assumed to
be like that of a 3-month-old child. At age 17 years, he had no speech,
was hypotonic, and had brown, coarse hair. Both the proband and his
cousin with the same less-severe symptoms had a deletion in the ATP7A
gene encompassing exons 3 and 4.

Paulsen et al. (2006) investigated the functional effect of the large
frameshift deletion in ATP7A including exons 3 and 4 identified in a
patient with Menkes disease with unexpectedly mild symptoms and long
survival (Tumer et al., 2003). The mutated transcript contained a
premature termination codon after 46 codons. Although such transcripts
are generally degraded by nonsense-mediated mRNA decay (NMD), it was
established by real-time PCR quantification that the transcript in this
instance was protected from degradation. A combination of in vitro
translation, recombinant expression, and immunocytochemical analysis
provided evidence that the mutant transcript was protected from
degradation because of reinitiation of protein translation. The findings
suggested that reinitiation takes place at 2 downstream internal codons.
The putative N terminally truncated proteins contained only
copper-binding site 5 (CBS5) and CBS6. Cellular localization and
copper-dependent trafficking of the major part of endogenous and
recombinant ATP7 mutant proteins were similar to the wildtype ATP7A
protein. Furthermore, the mutant cDNA was able to rescue a yeast strain
lacking the homologous gene, CCC2. In summary, Paulsen et al. (2006)
proposed that reinitiation of the NMD-resistant mutant transcript leads
to the synthesis of N terminally truncated and at least partially
functional Menkes proteins missing CBS1 through CBS4. Thus a mutation
that would have been assumed to be null is not.

.0013
OCCIPITAL HORN SYNDROME
ATP7A, ASN1304SER

In 2 brothers with occipital horn syndrome (304150) and their carrier
mother, Tang et al. (2006) identified an A-to-G transition at nucleotide
4056 in exon 20 of the ATP7A gene, resulting in an asparagine-to-serine
substitution at codon 1304 (N1304S). This mutation was not identified in
50 normal control chromosomes. Tang et al. (2006) showed evidence of 33%
residual copper transport by the N1304S mutant allele in a yeast
complementation assay.

.0014
MENKES DISEASE
ATP7A, ARG201TER

In a boy with Menkes disease (309400) and unusually favorable response
to early copper treatment, Kaler et al. (2009) identified a 746C-T
transition in exon 3 of the ATP7A gene, resulting in an arg201-to-ter
(R201X) substitution. Western blot analysis of patient fibroblasts
showed small amounts of the full-length 178-kD protein. In vitro studies
in yeast showed that the mutant protein retained functional copper
transport activity. Overall, the findings indicated a read-through of
the stop codon. Comparison with other yeast genes that show such
read-through mechanisms suggested that unique 5-prime sequences have a
role in nonsense suppression, and that mRNA structure may modulate
competition between eukaryotic release factors and suppressor tRNA. The
findings were consistent with the dramatic clinical response to
treatment in this patient, who was neurologically normal at age 11.5
years.

.0015
SPINAL MUSCULAR ATROPHY, DISTAL, X-LINKED 3
ATP7A, THR994ILE

In 10 affected males from a large Brazilian family with X-linked distal
spinal muscular atrophy-3 (SMAX3; 300489), Kennerson et al. (2010)
identified a hemizygous 2981C-T transition in exon 15 of the ATP7A gene,
resulting in a thr994-to-ile (T994I) substitution in a highly conserved
residue in the C terminus of the protein that did not disrupt critical
functional domains. The mutation was not found in 800 ethnically matched
controls. The family had previously been reported by Takata et al.
(2004). Immunocytochemical studies showed that the T994I-mutant protein
had impaired intracellular trafficking compared to control, with some of
the mutant protein remaining in the Golgi apparatus after exposure to
copper. The findings suggested that the mutation resulted in impaired
copper transport into the secretory pathway for incorporation into
nascent proproteins, perhaps due to reduced conformational flexibility.
Kennerson et al. (2010) suggested that the late onset of distal muscular
atrophy implies that the T994I mutation produced attenuated effects that
required years to provoke pathologic consequences. Motor neurons may be
particularly sensitive to perturbations in copper homeostasis or copper
deficiency, which may impair normal axonal growth and synaptogenesis.

.0016
SPINAL MUSCULAR ATROPHY, DISTAL, X-LINKED 3
ATP7A, PRO1386SER

In 9 affected males from a large North American family with X-linked
distal spinal muscular atrophy-3 (SMAX3; 300489), previously reported by
Kennerson et al. (2009), Kennerson et al. (2010) identified a hemizygous
4156C-T transition in exon 22 of the ATP7A gene, resulting in a
pro1386-to-ser (P1386S) substitution in a highly conserved residue in
the C terminus. The mutation was not found in 800 ethnically matched
controls. Immunocytochemical analyses showed that the P1386S-mutant
protein demonstrated impaired intracellular trafficking compared to
control, with some mutant protein remaining in the Golgi apparatus after
exposure to copper. Cultured fibroblasts carrying the P1386S mutation
had steady-state copper levels that were intermediate between normal
control and classic Menkes disease (309400). The growth of yeast
transformed with the P1386S allele was less than that of wildtype at all
temperatures. The findings suggested that the mutation resulted in
impaired copper transport into the secretory pathway for incorporation
into nascent proproteins, perhaps due to reduced conformational
flexibility. Kennerson et al. (2010) suggested that the late onset of
distal muscular atrophy implies that the P1386S mutation produced
attenuated effects that required years to provoke pathologic
consequences. Motor neurons may be particularly sensitive to
perturbations in copper homeostasis or copper deficiency, which may
impair normal axonal growth and synaptogenesis.

*FIELD* RF
1. Cecchi, C.; Biasotto, M.; Tosi, M.; Avner, P.: The mottled mouse
as a model for human Menkes disease: identification of mutations in
the Atp7a gene. Hum. Molec. Genet. 6: 425-433, 1997. Note: Erratum:
Hum. Molec. Genet. 6: 829 only, 1997.

2. Chelly, J.; Tumer, Z.; Tonnesen, T.; Petterson, A.; Ishikawa-Brush,
Y.; Tommerup, N.; Horn, N.; Monaco, A. P.: Isolation of a candidate
gene for Menkes disease that encodes a potential heavy metal binding
protein. Nature Genet. 3: 14-19, 1993.

3. Christodoulou, J.; Danks, D. M.; Sarkar, B.; Baerlocher, K. E.;
Casey, R.; Horn, N.; Tumer, Z.; Clarke, J. T. R.: Early treatment
of Menkes disease with parenteral cooper (sic)-histidine: long-term
follow-up of four treated patients. Am. J. Med. Genet. 76: 154-164,
1998.

4. Cobbold, C.; Coventry, J.; Ponnambalam, S.; Monaco, A. P.: The
Menkes disease ATPase (ATP7A) is internalized via a Rac1-regulated,
clathrin- and caveolae-independent pathway. Hum. Molec. Genet. 12:
1523-1533, 2003.

5. Cobbold, C.; Ponnambalam, S.; Francis, M. J.; Monaco, A. P.: Novel
membrane traffic steps regulate the exocytosis of the Menkes disease
ATPase. Hum. Molec. Genet. 11: 2855-2866, 2002.

6. Dagenais, S. L.; Adam, A. N.; Innis, J. W.; Glover, T. W.: A novel
frameshift mutation in exon 23 of ATP7A (MNK) results in occipital
horn syndrome and not in Menkes disease. Am. J. Hum. Genet. 69:
420-427, 2001.

7. Dierick, H. A.; Ambrosini, L.; Spencer, J.; Glover, T. W.; Mercer,
J. F. B.: Molecular structure of the Menkes disease gene (ATP7A). Genomics 28:
462-469, 1995.

8. Francis, M. J.; Jones, E. E.; Levy, E. R.; Ponnambalam, S.; Chelly,
J.; Monaco, A. P.: A Golgi localization signal identified in the
Menkes recombinant protein. Hum. Molec. Genet. 7: 1245-1252, 1998.

9. Gerard-Blanluet, M.; Birk-Moller, L.; Caubel, I.; Gelot, A.; Billette
de Villemeur, T.; Horn, N.: Early development of occipital horns
in a classical Menkes patient. (Letter) Am. J. Med. Genet. 130A:
211-213, 2004. Note: Erratum: Am. J. Med. Genet. 134A: 346 only, 2005.

10. Gourdon, P.; Liu, X.-Y.; Skjorringe, T.; Morth, J. P.; Moller,
L. B.; Pedersen, B. P.; Nissen, P.: Crystal structure of a copper-transporting
PIB-type ATPase. Nature 475: 59-64, 2011.

11. Grimes, A.; Hearn, C. J.; Lockhart, P.; Newgreen, D. F.; Mercer,
J. F. B.: Molecular basis of the brindled mouse mutant (Mo-br): a
murine model of Menkes disease. Hum. Molec. Genet. 6: 1037-1042,
1997.

12. Gu, Y.-H.; Kodama, H.; Murata, Y.; Mochizuki, D.; Yanagawa, Y.;
Ushijima, H.; Shiba, T.; Lee, C.-C.: ATP7A gene mutations in 16 patients
with Menkes disease and a patient with occipital horn syndrome. Am.
J. Med. Genet. 99: 217-222, 2001.

13. Horn, N.: Personal Communication. Copenhagen, Denmark 2/25/1999.

14. Jankov, R. P.; Boerkoel, C. F.; Hellmann, J.; Sirkin, W. L.; Tumer,
Z.; Horn, N.; Feigenbaum, A.: Lethal neonatal Menkes' disease with
severe vasculopathy and fractures. Acta Paediat. 87: 1297-1300,
1998.

15. Kaler, S. G.; Buist, N. R. M.; Holmes, C. S.; Goldstein, D. S.;
Miller, R. C.; Gahl, W. A.: Early copper therapy in classic Menkes
disease patients with a novel splicing mutation. Ann. Neurol. 38:
921-928, 1995.

16. Kaler, S. G.; Das, S.; Levinson, B.; Goldstein, D. S.; Holmes,
C. S.; Patronas, N. J.; Packman, S.; Gahl, W. A.: Successful early
copper therapy in Menkes disease associated with a mutant transcript
containing a small in-frame deletion. Biochem. Molec. Med. 57: 37-46,
1996.

17. Kaler, S. G.; Gallo, L. K.; Proud, V. K.; Percy, A. K.; Mark,
Y.; Segal, N. A.; Goldstein, D. S.; Holmes, C. S.; Gahl, W. A.: Occipital
horn syndrome and a mild Menkes phenotype associated with splice site
mutations at the MNK locus. Nature Genet. 8: 195-202, 1994.

18. Kaler, S. G.; Tang, J.; Donsante, A.; Kaneski, C. R.: Translational
read-through of a nonsense mutation in ATP7A impacts treatment outcome
in Menkes disease. Ann. Neurol. 65: 108-113, 2009.

19. Kennerson, M.; Nicholson, G.; Kowalski, B.; Krajewski, K.; El-Khechen,
D.; Feely, S.; Chu, S.; Shy, M.; Garbern, J.: X-linked distal hereditary
motor neuropathy maps to the DSMAX locus on chromosome Xq13.1-q21. Neurology 72:
246-252, 2009.

20. Kennerson, M. L.; Nicholson, G. A.; Kaler, S. G.; Kowalski, B.;
Mercer, J. F. B.; Tang, J.; Llanos, R. M.; Chu, S.; Takata, R. I.;
Speck-Martins, C. E.; Baets, J.; Almeida-Souza, L.; and 10 others
: Missense mutations in the copper transporter gene ATP7A cause X-linked
distal hereditary motor neuropathy. Am. J. Hum. Genet. 86: 343-352,
2010.

21. Kim, B.-E.; Smith, K.; Meagher, C. K.; Petris, M. J.: A conditional
mutation affecting localization of the Menkes disease copper ATPase:
suppression by copper supplementation. J. Biol. Chem. 277: 44079-44084,
2002.

22. Kim, B.-E.; Smith, K.; Petris, M. J.: A copper treatable Menkes
disease mutation associated with defective trafficking of a functional
Menkes copper ATPase. J. Med. Genet. 40: 290-295, 2003.

23. Kuo, Y.-M.; Gitschier, J.; Packman, S.: Developmental expression
of the mouse mottled and toxic milk genes suggests distinct functions
for the Menkes and Wilson disease copper transporters. Hum. Molec.
Genet. 6: 1043-1049, 1997.

24. Levinson, B.; Conant, R.; Schnur, R.; Das, S.; Packman, S.; Gitschier,
J.: A repeated element in the regulatory region of the MNK gene and
its deletion in a patient with occipital horn syndrome. Hum. Molec.
Genet. 5: 1737-1742, 1996.

25. Levinson, B.; Vulpe, C.; Elder, B.; Martin, C.; Verley, F.; Packman,
S.; Gitschier, J.: The mottled gene is the mouse homologue of the
Menkes disease gene. Nature Genet. 6: 369-373, 1994.

26. Mentzel, H. J.; Seidel, J.; Vogt, S.; Vogt, L.; Kaiser, W. A.
: Vascular complications (splenic and hepatic artery aneurysms) in
the occipital horn syndrome: report of a patient and review of the
literature. Pediat. Radiol. 29: 19-22, 1999.

27. Mercer, J. F. B.; Grimes, A.; Ambrosini, L.; Lockhart, P.; Paynter,
J. A.; Dierick, H.; Glover, T. W.: Mutations in the murine homologue
of the Menkes gene in dappled and blotchy mice. Nature Genet. 6:
374-378, 1994.

28. Mercer, J. F. B.; Livingston, J.; Hall, B.; Paynter, J. A.; Begy,
C.; Chandrasekharappa, S.; Lockhart, P.; Grimes, A.; Bhave, M.; Siemieniak,
D.; Glover, T. W.: Isolation of a partial candidate gene for Menkes
disease by positional cloning. Nature Genet. 3: 20-25, 1993.

29. Moizard, M.-P.; Ronce, N.; Blesson, S.; Bieth, E.; Burglen, L.;
Mignot, C.; Mortemousque, I.; Marmin, N.; Dessay, B.; Danesino, C.;
Feillet, F.; Castelnau, P.; Toutain, A.; Moraine, C.; Raynaud, M.
: Twenty-five novel mutations including duplications in the ATP7A
gene. Clin. Genet. 79: 243-253, 2011.

30. Moller, L. B.; Bukrinsky, J. T.; 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. 26: 84-93, 2005.

31. Moller, L. B.; Tumer, Z.; Lund, C.; Petersen, C.; Cole, T.; Hanusch,
R.; Seidel, J.; Jensen, L. R.; Horn, N.: Similar splice-site mutations
of the ATP7A gene lead to different phenotypes: classical Menkes disease
or occipital horn syndrome. Am. J. Hum. Genet. 66: 1211-1220, 2000.

32. Packman, S.; Enns, G. M.; O'Toole, C. J.; Cox, V. A.; Golabi,
M.: Atypical severe Menkes disease presenting with neonatal cutis
laxa. (Abstract) Am. J. Hum. Genet. 61 (suppl.): A258 only, 1997.

33. Paulsen, M.; Lund, C.; Akram, Z.; Winther, J. R.; Horn, N.; Moller,
L. B.: Evidence that translation reinitiation leads to a partially
functional Menkes protein containing two copper-binding sites. Am.
J. Hum. Genet. 79: 214-229, 2006.

34. Petris, M. J.; Camakaris, J.; Greenough, M.; LaFontaine, S.; Mercer,
J. F. B.: A C-terminal di-leucine is required for localization of
the Menkes protein in the trans-Golgi network. Hum. Molec. Genet. 7:
2063-2071, 1998.

35. Petris, M. J.; Strausak, D.; Mercer, J. F. B.: The Menkes copper
transporter is required for the activation of tyrosinase. Hum. Molec.
Genet. 9: 2845-2851, 2000.

36. Poulsen, L.; Horn, N.; Moller, L. B.: X-linked recessive Menkes
disease: carrier detection in the case of a partial gene deletion. Clin.
Genet. 62: 440-448, 2002.

37. Poulsen, L.; Horn, N.; Tumer, Z.; Heilstrup, H.; Lund, C.; Moller,
L. B.: X-linked recessive Menkes disease: identification of partial
gene deletions in affected males. Clin. Genet. 62: 449-457, 2002.

38. Qian, Y.; Tiffany-Castiglioni, E.; Harris, E. D.: Sequence of
a Menkes-type Cu-transporting ATPase from rat C6 glioma cells: comparison
of the rat protein with other mammalian Cu-transporting ATPases. Molec.
Cell. Biochem. 181: 49-61, 1998.

39. Reed, V.; Boyd, Y.: Mutation analysis provides additional proof
that mottled is the mouse homologue of Menkes' disease. Hum. Molec.
Genet. 6: 417-423, 1997.

40. Ronce, N.; Moizard, M.-P.; 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. (Letter) Am.
J. Hum. Genet. 61: 233-238, 1997.

41. Schlief, M. L.; West, T.; Craig, A. M.; Holtzman, D. M.; Gitlin,
J. D.: Role of the Menkes copper-transporting ATPase in NMDA receptor-mediated
neuronal toxicity. Proc. Nat. Acad. Sci. 103: 14919-14924, 2006.

42. Setty, S. R. G.; Tenza, D.; Sviderskaya, E. V.; Bennett, D. C.;
Raposo, G.; Marks, M. S.: Cell-specific ATP7A transport sustains
copper-deficient tyrosinase activity in melanosomes. Nature 454:
1142-1146, 2008.

43. Takata, R. I.; Speck Martins, C. E.; Passosbueno, M. R.; Abe,
K. T.; Nishimura, A. L.; Morvalina Da Silva, M. D.; Monteiro, A.,
Jr.; Lima, M. I.; Kok, F.; Zatz, M.: A new locus for recessive distal
spinal muscular atrophy at Xq13.1-q21. J. Med. Genet. 41: 224-229,
2004.

44. Tang, J.; Robertson, S.; Lem, K. E.; Godwin, S. C.; Kaler, S.
G.: Functional copper transport explains neurologic sparing in occipital
horn syndrome. Genet. Med. 8: 711-718, 2006.

45. Tsukahara, M.; Imaizumi, K.; Kawai, S.; Kajii, T.: Occipital
horn syndrome: report of a patient and review of the literature. Clin.
Genet. 45: 32-35, 1994.

46. 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. 60: 63-71, 1997.

47. Tumer, Z.; Moller, L. B.; Horn, N.: Screening of 383 unrelated
patients affected with Menkes disease and finding of 57 gross deletions
in ATP7A. Hum. Mutat. 22: 457-464, 2003.

48. Tumer, Z.; Vural, B.; Tonnesen, T.; Chelly, J.; Monaco, A. P.;
Horn, N.: Characterization of the exon structure of the Menkes disease
gene using vectorette PCR. Genomics 26: 437-442, 1995.

49. Vulpe, C.; Levinson, B.; Whitney, S.; Packman, S.; Gitschier,
J.: Isolation of a candidate gene for Menkes disease and evidence
that it encodes a copper-transporting ATPase. Nature Genet. 3: 7-13,
1993. Note: Erratum: Nature Genet. 3: 273 only, 1993.

*FIELD* CN
Ada Hamosh - updated: 9/6/2011
Cassandra L. Kniffin - updated: 7/21/2011
Cassandra L. Kniffin - updated: 4/19/2010
Cassandra L. Kniffin - updated: 7/14/2009
Ada Hamosh - updated: 9/24/2008
Ada Hamosh - updated: 7/25/2007
Patricia A. Hartz - updated: 1/26/2007
Cassandra L. Kniffin - updated: 8/9/2006
Victor A. McKusick - updated: 7/10/2006
George E. Tiller - updated: 4/22/2005
Cassandra L. Kniffin - reorganized: 3/15/2005
Victor A. McKusick - updated: 11/23/2004
George E. Tiller - updated: 3/31/2004
Victor A. McKusick - updated: 1/22/2004
Victor A. McKusick - updated: 2/12/2003
Victor A. McKusick - updated: 12/26/2002
Victor A. McKusick - updated: 8/30/2001
Victor A. McKusick - updated: 3/13/2001
George E. Tiller - updated: 2/5/2001
Victor A. McKusick - updated: 4/12/2000
Victor A. McKusick - updated: 3/12/1999
Victor A. McKusick - updated: 1/7/1999
Victor A. McKusick - updated: 10/24/1997
Victor A. McKusick - updated: 8/20/1997
Victor A. McKusick - updated: 4/15/1997
Victor A. McKusick - updated: 2/5/1997
Moyra Smith - updated: 1/28/1997

*FIELD* CD
Victor A. McKusick: 2/4/1996

*FIELD* ED
carol: 09/11/2013
terry: 4/4/2013
terry: 11/28/2012
alopez: 8/8/2012
terry: 4/12/2012
alopez: 9/7/2011
terry: 9/6/2011
wwang: 7/27/2011
ckniffin: 7/21/2011
wwang: 4/28/2010
ckniffin: 4/19/2010
carol: 1/21/2010
wwang: 7/29/2009
ckniffin: 7/14/2009
alopez: 9/26/2008
terry: 9/24/2008
terry: 12/17/2007
alopez: 7/31/2007
terry: 7/25/2007
mgross: 1/26/2007
wwang: 8/22/2006
ckniffin: 8/9/2006
alopez: 7/14/2006
terry: 7/10/2006
tkritzer: 4/22/2005
tkritzer: 3/15/2005
ckniffin: 3/1/2005
tkritzer: 11/30/2004
terry: 11/23/2004
tkritzer: 3/31/2004
cwells: 1/27/2004
terry: 1/22/2004
carol: 2/27/2003
tkritzer: 2/24/2003
terry: 2/12/2003
carol: 1/2/2003
tkritzer: 12/27/2002
terry: 12/26/2002
ckniffin: 5/15/2002
carol: 4/29/2002
cwells: 10/18/2001
cwells: 9/20/2001
cwells: 9/17/2001
terry: 8/30/2001
carol: 3/20/2001
cwells: 3/20/2001
terry: 3/13/2001
cwells: 2/5/2001
cwells: 1/30/2001
terry: 4/18/2000
carol: 4/14/2000
terry: 4/12/2000
terry: 6/8/1999
carol: 3/15/1999
terry: 3/12/1999
carol: 1/18/1999
terry: 1/7/1999
dkim: 9/10/1998
mark: 11/4/1997
terry: 10/28/1997
alopez: 10/27/1997
terry: 10/24/1997
terry: 8/25/1997
terry: 8/20/1997
jenny: 8/19/1997
jenny: 4/15/1997
terry: 4/10/1997
mark: 2/5/1997
mark: 1/29/1997
terry: 1/28/1997
mark: 1/28/1997
terry: 1/15/1997
joanna: 8/8/1996
mark: 6/13/1996
mark: 3/4/1996
mark: 2/20/1996
joanna: 2/4/1996

MIM 300489
*RECORD*
*FIELD* NO
300489
*FIELD* TI
#300489 SPINAL MUSCULAR ATROPHY, DISTAL, X-LINKED 3; SMAX3
;;SPINAL MUSCULAR ATROPHY, DISTAL, X-LINKED RECESSIVE;;
read moreDSMAX
*FIELD* TX
A number sign (#) is used with this entry because X-linked distal spinal
muscular atrophy-3 (SMAX3) is caused by mutation in the copper transport
gene ATP7A (300011).

For a discussion of genetic heterogeneity of distal spinal muscular
atrophy, see 158590.

CLINICAL FEATURES

Takata et al. (2004) reported a white Brazilian family in which 17 males
were affected with a distal form of spinal muscular atrophy affecting
both the upper and lower limbs. The disorder was transmitted in an
X-linked recessive pattern of inheritance. In 6 of 9 patients who were
examined, age at onset ranged from 1 to 10 years, and the first detected
symptom was foot deformity (pes cavus or pes varus); gait instability
was reported in 2 other individuals. Subsequently, distal lower limb
weakness and atrophy were observed, and finally, the hands were
affected. Despite the large clinical variability, the disease
progression was very slow and independent gait was maintained even late
in life. There was no cognitive, pyramidal, or sensory impairment. EMG
showed chronic denervation, muscle biopsy showed a neurogenic pattern,
and sural nerve biopsy was normal.

Kennerson et al. (2009) reported a 3-generation family with X-linked
distal motor neuropathy. Age at onset ranged from 10 to 30 years and was
characterized by distal motor weakness particularly of the lower limbs
that resulted in gait abnormalities and atrophy of lower limb muscles.
There was either little or no sensory involvement in affected
individuals. Obligate female heterozygotes were unaffected.

MAPPING

In the family reported by Takata et al. (2004), linkage analysis
identified a disease locus in a 4.3-cM region between markers DXS8046
and DXS990 at chromosome Xq13.1-q21 (maximum 2-point lod score of 5.74
at marker DXS986).

By linkage analysis of a family with X-linked distal motor neuropathy,
Kennerson et al. (2009) refined the DSMAX locus to a 1.44-cM (14.2-Mb)
interval on chromosome Xq13.1-q21 between DXS8046 and DXS8114. Sequence
analysis excluded mutation in the GJB1 gene (304040) on Xq13, and
high-resolution melt analysis excluded mutations in the coding region of
9 additional candidate genes. Kennerson et al. (2009) postulated that
the disorder in this family was allelic to that reported by Takata et
al. (2004) despite the earlier age of onset in the latter family.

MOLECULAR GENETICS

In affected members of 2 families previously reported by Takata et al.
(2004) and Kennerson et al. (2009), Kennerson et al. (2010) identified 2
different mutations in the ATP7A gene: T994I (300011.0015) and P1386S
(300011.0016), respectively. In vitro functional expression assays
indicated that the mutations resulted in impaired copper transport into
the secretory pathway for incorporation into nascent proproteins,
perhaps due to reduced conformational flexibility. Kennerson et al.
(2010) suggested that the late onset of distal muscular atrophy implies
that these mutations produced attenuated effects that required years to
provoke pathologic consequences. Motor neurons may be particularly
sensitive to perturbations in copper homeostasis or copper deficiency,
which may impair normal axonal growth and synaptogenesis.

*FIELD* RF
1. Kennerson, M.; Nicholson, G.; Kowalski, B.; Krajewski, K.; El-Khechen,
D.; Feely, S.; Chu, S.; Shy, M.; Garbern, J.: X-linked distal hereditary
motor neuropathy maps to the DSMAX locus on chromosome Xq13.1-q21. Neurology 72:
246-252, 2009.

2. Kennerson, M. L.; Nicholson, G. A.; Kaler, S. G.; Kowalski, B.;
Mercer, J. F. B.; Tang, J.; Llanos, R. M.; Chu, S.; Takata, R. I.;
Speck-Martins, C. E.; Baets, J.; Almeida-Souza, L.; and 10 others
: Missense mutations in the copper transporter gene ATP7A cause X-linked
distal hereditary motor neuropathy. Am. J. Hum. Genet. 86: 343-352,
2010.

3. Takata, R. I.; Speck Martins, C. E.; Passosbueno, M. R.; Abe, K.
T.; Nishimura, A. L.; Morvalina Da Silva, M. D.; Monteiro, A., Jr.;
Lima, M. I.; Kok, F.; Zatz, M.: A new locus for recessive distal
spinal muscular atrophy at Xq13.1-q21. J. Med. Genet. 41: 224-229,
2004.

*FIELD* CS
INHERITANCE:
X-linked recessive

SKELETAL:
[Feet];
Pes cavus;
Pes varus

NEUROLOGIC:
[Central nervous system];
Gait instability;
Muscle weakness, distal;
Muscle atrophy, distal;
Lower limbs affected before upper limbs;
Hyporeflexia;
EMG shows neurogenic changes;
Muscle biopsy shows neurogenic changes;
[Peripheral nervous system];
Peripheral nerve biopsy is normal;
Mild distal sensory impairment (in some)

MISCELLANEOUS:
Onset in first decade;
Adult onset may also occur;
Slow disease progression;
Affected individuals remain ambulatory in old age

MOLECULAR BASIS:
Caused by mutation in the ATPase, Cu(2+)-transporting, alpha polypeptide
(ATP7A, 300011.0015)

*FIELD* CN
Cassandra L. Kniffin - updated: 4/19/2010

*FIELD* CD
Cassandra L. Kniffin: 3/31/2004

*FIELD* ED
joanna: 05/04/2010
ckniffin: 4/19/2010
ckniffin: 3/31/2004

*FIELD* CN
Cassandra L. Kniffin - updated: 3/12/2009

*FIELD* CD
Cassandra L. Kniffin: 3/31/2004

*FIELD* ED
wwang: 04/28/2010
ckniffin: 4/19/2010
wwang: 3/24/2009
ckniffin: 3/12/2009
alopez: 6/26/2008
joanna: 4/21/2004
tkritzer: 4/21/2004
ckniffin: 3/31/2004

MIM 304150
*RECORD*
*FIELD* NO
304150
*FIELD* TI
#304150 OCCIPITAL HORN SYNDROME; OHS
;;CUTIS LAXA, X-LINKED, FORMERLY;;
EHLERS-DANLOS SYNDROME, OCCIPITAL HORN TYPE, FORMERLY;;
read moreEDS IX, FORMERLY;;
EDS9, FORMERLY
*FIELD* TX
A number sign (#) is used with this entry because occipital horn
syndrome (OHS) is caused by mutation in the gene encoding
Cu(2+)-transporting ATPase, alpha polypeptide (ATP7A; 300011). Menkes
syndrome (309400) is caused by mutation in the same gene.

DESCRIPTION

Occipital horn syndrome is a rare connective tissue disorder
characterized by hyperelastic and bruisable skin, hernias, bladder
diverticula, hyperextensible joints, varicosities, and multiple skeletal
abnormalities. The disorder is sometimes accompanied by mild neurologic
impairment, and bony abnormalities of the occiput are a common feature,
giving rise to the name (summary by Das et al., 1995).

CLINICAL FEATURES

Lazoff et al. (1975) described an unusual syndrome in an 11-year-old
male and 2 maternal uncles. Bony 'horns,' symmetrically situated on each
side of the foramen magnum and pointing caudad, were demonstrable
radiographically. A lifelong history of frequent loose stools,
obstructive uropathy requiring in 1 uncle ileal loop diversion, and mild
mental retardation were other features. Some suspicion that a relative
through the maternal grandfather had the same condition (which could not
be confirmed because of lack of cooperation) meant that autosomal
dominant inheritance with reduced penetrance could not be excluded.

Byers et al. (1976) found deficiency of lysyl oxidase in affected males
in a family with apparent X-linked cutis laxa. Three affected males were
observed, each in a different sibship connected through females who as
children showed joint laxity but outgrew it. Hooked nose and long
philtrum typical of cutis laxa were described. In 1 case, pectus
excavatum and carinatum were sufficiently severe to require surgical
repair shortly after birth. Two cousins were brought to medical
attention because of recurrent urinary tract infection due to multiple
large diverticula of the bladder.

MacFarlane et al. (1980) described 2 kindreds with an X-linked disorder
that in general appeared to fall into the Ehlers-Danlos category but had
some unusual features such as bladder diverticula, bladder neck
obstruction, marked varicosities, and, by x-ray, occipital horns, short
broad clavicles, and fused carpal bones. Hall (1980) found that the
children studied with Byers et al. (1976) also had occipital horns, and
diarrhea, a feature found in MacFarlane's families, was also present.
Thus, these are probably the same disorder. The age at which the
affected persons were studied may have been a factor in determining
whether the disorder was labeled cutis laxa or EDS. Low levels of
ceruloplasmin (117700) and serum copper were found in these cases,
suggesting that, like Menkes syndrome, it may be a disorder of copper
metabolism rather than a primary defect of lysyl oxidase.

Hollister (1981) pointed out that the patients show hypermobility of the
finger joints but limitation of extension of the elbows.

Kuivaniemi et al. (1982) studied 2 brothers with bladder diverticula,
inguinal hernias, slight skin laxity and hyperextensibility, and
skeletal abnormalities, including occipital exostoses. Lysyl oxidase
activity was low in the medium of cultured skin fibroblasts, and
conversion of newly synthesized collagen into the insoluble form was
reduced. Copper concentrations were markedly elevated in cultured skin
fibroblasts but decreased in serum and hair. Serum ceruloplasmin levels
were low.

Kaitila et al. (1982) suggested that this disorder may be allelic to
Menkes disease.

Peltonen et al. (1983) found many similar abnormalities of copper and
collagen metabolism in the cultured fibroblasts of 13 patients with
Menkes syndrome and 2 patients with OHS (then called EDS IX). In both
disorders, fibroblasts had markedly increased copper content and rate of
incorporation of (64)Cu, and accumulation was in metallothionein or a
metallothionein-like protein as previously established for Menkes cells.
Histochemical staining showed that copper was distributed uniformly
throughout the cytoplasm in both cell types, this location being
consistent with accumulation in metallothionein. Both fibroblast types
showed very low lysyl oxidase activity and increased extractability of
newly synthesized collagen, but no abnormality in cell viability,
duplication rate, prolyl 4-hydroxylase activity, or collagen synthesis
rate. Skin biopsy specimens from one EDS IX patient showed the same
abnormalities in lysyl oxidase activity and collagen extractability.
Fibroblasts of the mother of EDS IX patients showed increased (64)Cu
incorporation.

Allelism of occipital horn syndrome and Menkes syndrome was demonstrated
in a definitive way by Das et al. (1995) who identified hemizygosity for
a mutation in the copper-transporting ATPase that is mutant in Menkes
syndrome. One of the mild mottled mutants in the mouse, 'blotchy,'
symbolized Mo-blo, exhibits connective tissue abnormalities reminiscent
of those seen in OHS patients, including weak skin and bone
abnormalities. In blotchy males, hindlegs are occasionally deformed,
vibrissae are kinked at birth, crosslinking of skin collagen and aortic
elastin is defective, and death frequently results from aortic rupture.
Das et al. (1995) identified similar splicing mutations in both the
blotchy mouse and cases of the occipital horn syndrome. Das et al.
(1995) reported 2 OHS patients in each of whom there was a deletion of 1
exon in the ATP7A gene; one deletion was caused by an A-to-G transition
at the -4 position of the splice acceptor site 5-prime of the skipped
exon, and the other deletion was caused by a G-to-A transition at the +5
splice donor site following the skipped exon. The first patient had
presented to a genetics clinic at the age of 14 years for evaluation of
musculoskeletal abnormalities and recurrent bladder rupture. In the
neonatal period, mild hypotonia and, on radiographs, cranial contour
abnormalities and wormian bones had been observed. There had been
numerous orthopedic interventions, including osteotomies for leg
straightening and treatment for multiple compression fractures of the
vertebrae. Recurrent bladder rupture, bladder diverticula, vesicular
calcium stones, and atonic bladder required intermittent
catheterization. Examination showed dolichocephaly, prominent and simple
ears, downslanting palpebral fissures with bilateral ptosis, dental
crowding, pectus carinatum, cutis laxa, and muscle wasting. Neurologic
status, including cognition, was normal. Serum ceruloplasmin was
slightly low. Radiographs demonstrated osteopenia, dislocated radial
heads, and characteristic occipital horns. Radiocopper accumulation in
fibroblasts was elevated. The second patient presented to a medical
genetics clinic at the age of 15 years, at which time he was
wheelchair-bound because of genu valgum and coxa vara deformities. He
was mentally retarded. The skin had a cobblestone appearance with
hyperelasticity at the elbows and without skin friability. There was
laxity of the interphalangeal joints with contractures at the elbows and
knees. Serum ceruloplasmin and copper determinations were normal.
Radiographs showed bilateral occipital horns. The large diverticula of
the bladder were demonstrated. X-rays of the skeleton showed
osteoporosis, fusion anomalies in the wrist, and dysplasia of the radius
and ulna, with dislocation of the radius at the elbow.

That the occipital horn syndrome has ramifications beyond connective
tissue is suggested by peculiarities of personality. Unlike patients
with Menkes disease, most patients with OHS have mild mental
retardation. Wakai et al. (1993) described the first Japanese case in a
34-year-old man who had psychomotor retardation and seizures since early
childhood. At the time of study, he had severe mental retardation and
generalized muscular atrophy, in addition to characteristic facial
features, hyperelasticity of the skin, and joint subluxation. Laboratory
studies demonstrated low serum copper and ceruloplasmin levels as well
as intestinal nonabsorption of copper. Radiographic studies showed
occipital exostoses, bladder diverticula, tortuosity of peripheral
veins, and osteoporosis. Lysyl oxidase activity was decreased in skin.

Tsukahara et al. (1994) described OHS in an 18-year-old Japanese boy. In
addition to bilateral occipital exostosis, radiologic features were
prominent mandibular angles, short and broad clavicles with
'hammer-shaped' distal ends, long bones with thin and undercalcified
cortices, coalescence between the hamate and capitate bones and between
the greater and lesser multiangular bones, and coxa valga. Since birth
the patient had had chronic diarrhea (5-10 times/day) that did not
respond to antidiarrheal drugs. Tsukahara et al. (1994) found reports of
a total of 21 patients, all male. Mild manifestations were described in
some of the mothers or aunts of patients (Herman et al., 1992).

In a study of cultured cells from patients with EDS IX, Kuivaniemi et
al. (1985) could not demonstrate that there was secreted into the medium
or contained in the cell any significant amounts of copper-deficient,
catalytically inactive lysyl oxidase protein. Although the rapid
degradation of a mutant protein could not be excluded, the authors
favored the idea that synthesis of the lysyl oxidase protein is
impaired. Levinson et al. (1993) found a marked reduction in expression
of a copper-transporting ATPase gene, which Vulpe et al. (1993) had
designated Mc1 and proposed as a candidate gene for Menkes disease, in
Northern blots of RNA extracted from fibroblasts of 2 unrelated males
with X-linked cutis laxa.

Blackston et al. (1987) studied copper storage and copper retention in
females at risk of being heterozygous. In the mother of an affected
male, they found in skin fibroblasts a level of total copper and a value
for retention of copper that were outside the normal. The findings in a
sister of the proband indicated that she was homozygous normal.

Khakoo et al. (1997) reported 2 phenotypically similar patients with
primary cutis laxa associated with deficiency of lysyl oxidase. Previous
reports of congenital cutis laxa had concerned mainly the X-linked form
of the disorder, which is characterized by typical occipital osseous
projections and an abnormality of copper metabolism. The 2 patients
reported by Khakoo et al. (1997) showed no occipital projections and had
normal copper metabolism. Furthermore, they showed wormian bones, and
the family pattern of inheritance was thought to be consistent with an
autosomal recessive disorder. The first boy, 15 years old at the time of
report, was born with unusually translucent wrinkled skin with prominent
veins, generalized joint laxity, and a hooked nose. A large umbilical
hernia was repaired at 3 months of age. Lysyl oxidase deficiency was
demonstrated by study of cultured fibroblasts. Lax skin, generalized
joint laxity, and blue sclerae were consistently noted. The ears were
large with prominent lobes. At the age of 10, the skin had become
thicker without residual translucency. Wormian bones were demonstrated
in the lambdoid sutures and osteoporosis of the lumbar spine was found.
The mother's lysyl oxidase levels were approximately half normal. The
second boy was born to first-cousin parents of Pakistani origin. Again
the skin was lax at birth and the nose hooked, the joints of the hands
and feet were hypermobile, and wormian bones were demonstrated in the
lambdoid sutures. There was an irreducible, translocated left hip. Lysyl
oxidase activity was measured at 20% of normal. At 2 years of age, the
patient developed acute renal failure, owing to a vesicoureteric
obstruction causing gross bilateral hydroureters and hydronephrosis.
Bladder atonicity was also present. The ears were large, and radiographs
of the lumbar spine showed osteoporosis. Bilateral dislocatable
shoulders were also present in this boy, who was 5 years old at the time
of the report.

Tang et al. (2006) described 2 brothers with occipital horn syndrome.
The proband had occipital horns bilaterally at age 4 years, short broad
clavicles, broad and flat ilia, and dislocated radial heads. Both
brothers had genu valgum; the proband required bilateral tibial
osteotomies. Both brothers had coarse hair and hyperelastic skin but no
dysmorphic facial features. The mother, who carried the mutation present
in her sons, had had clubfoot requiring multiple surgeries as a young
child. She had coarse hair and mild hyperextensibility of the
metacarpophalangeal and interphalangeal joints, which was marked in her
sons.

MOLECULAR GENETICS

Kaler et al. (1994) reported a 15-year-old male with OHS who had an
A-to-G change at base 2642 of the MNK locus, predicting a neutral
glycine for serine substitution at nucleotide 833. Actually, this
mutation at the -2 exonic position of a splice donor site caused exon
skipping and activation of a cryptic splice acceptor site (300011.0002).
The authors suggested that maintenance of some normal splicing could
explain the relatively mild phenotype of this patient.

In a patient with OHS, Levinson et al. (1996) identified a 98-bp
deletion involving an upstream regulatory element of the MNK gene; see
300011.

Tang et al. (2006) described 2 brothers with occipital horn syndrome who
had a missense mutation (N1304S; 300011.0013) that had 33% residual
copper transport activity. Serum copper level was low, and ceruloplasmin
was at the low end of normal.

NOMENCLATURE

MacFarlane et al. (1980) suggested the designation Ehlers-Danlos
syndrome type IX. It was suggested at a workshop convened in Berlin by
Beighton (1986) that this disorder be removed from the Ehlers-Danlos
category (with the EDS IX number retired, as with MPS V and clotting
factor IV) and instead be placed in a category of disorders with
secondary changes in connective tissue due to a defect in copper
metabolism.

*FIELD* SA
Byers et al. (1980)
*FIELD* RF
1. Beighton, P.: Personal Communication. Cape Town, South Africa
9/26/1986.

2. Blackston, R. D.; Hirschhorn, K.; Elsas, L. J.: Ehlers-Danlos
syndrome (EDS), type IX: biochemical evidence for X-linkage. (Abstract) Am.
J. Hum. Genet. 41: A49, 1987.

3. Byers, P. H.; Narayanan, A. S.; Bornstein, P.; Hall, J. G.: An
X-linked form of cutis laxa due to deficiency of lysyloxidase. Birth
Defects Orig. Art. Ser. 12(5): 293-298, 1976.

4. Byers, P. H.; Siegel, R. C.; Holbrook, K. A.; Narayanan, A. S.;
Bornstein, P.; Hall, J. G.: X-linked cutis laxa: defective collagen
crosslink formation due to decreased lysyl oxidase activity. New
Eng. J. Med. 303: 61-65, 1980.

5. Das, S.; Levinson, B.; Vulpe, C.; Whitney, S.; Gitschier, J.; Packman,
S.: Similar splicing mutations of the Menkes/mottled copper-transporting
ATPase gene in occipital horn syndrome and the blotchy mouse. Am.
J. Hum. Genet. 56: 570-576, 1995.

6. Hall, J. G.: Personal Communication. Seattle, Wash. 1980.

7. Herman, T. E.; McAlister, W. H.; Boniface, A.; Whyte, M. P.: Occipital
horn syndrome: additional radiographic findings in two new cases. Pediat.
Radiol. 22: 363-365, 1992.

8. Hollister, D. W.: Clinical features of Ehlers-Danlos syndrome
types VIII and IX.In: Akeson, W.; Glimcher, M. J.; Bornstein, P.:
Proceeding of the Workshop on Inherited Connective Tissue Disorders.
New York: Elsevier/North Holland Press (pub.) 1981.

9. Kaitila, I. I.; Peltonen, L.; Kuivaniemi, H.; Palotie, A.; Elo,
J.; Kivirikko, K. I.: A skeletal and connective tissue disorder associated
with lysyl oxidase deficiency and abnormal copper metabolism.In: Papadatos,
C. J.; Bartsocas, C. S.: Skeletal Dysplasias. New York: Alan R.
Liss (pub.) 1982. Pp. 307-316.

10. Kaler, S. G.; Gallo, L. K.; Proud, V. K.; Percy, A. K.; Mark,
Y.; Segal, N. A.; Goldstein, D. S.; Holmes C. S.; Gahl, W. A.: Occipital
horn syndrome and a mild Menkes phenotype associated with splice site
mutations at the MNK locus. Nature Genet. 8: 195-202, 1994.

11. Khakoo, A.; Thomas, R.; Trompeter, R.; Duffy, P.; Price, R.; Pope,
F. M.: Congenital cutis laxa and lysyl oxidase deficiency. Clin.
Genet. 51: 109-114, 1997.

12. Kuivaniemi, H.; Peltonen, L.; Kivirikko, K. I.: Type IX Ehlers-Danlos
syndrome and Menkes syndrome: the decrease in lysyl oxidase activity
is associated with a corresponding deficiency in the enzyme protein. Am.
J. Hum. Genet. 37: 798-808, 1985.

13. Kuivaniemi, H.; Peltonen, L.; Palotie, A.; Kaitila, I.; Kivirikko,
K. I.: Abnormal copper metabolism and deficient lysyl oxidase activity
in a heritable connective tissue disorder. J. Clin. Invest. 69:
730-733, 1982.

14. Lazoff, S. G.; Rybak, J. J.; Parker, B. R.; Luzzatti, L.: Skeletal
dysplasia, occipital horns, intestinal malabsorption, and obstructive
uropathy--a new hereditary syndrome. Birth Defects Orig. Art. Ser. XI(5):
71-74, 1975.

15. Levinson, B.; Conant, R.; Schnur, R.; Das, S.; Packman, S.; Gitschier,
J.: A repeated element in the regulatory region of the MNK gene and
its deletion in a patient with occipital horn syndrome. Hum. Molec.
Genet. 5: 1737-1742, 1996.

16. Levinson, B.; Gitschier, J.; Vulpe, C.; Whitney, S.; Yang, S.;
Packman, S.: Are X-linked cutis laxa and Menkes disease allelic?
(Letter) Nature Genet. 3: 6, 1993.

17. MacFarlane, J. D.; Hollister, D. W.; Weaver, D. D.; Brandt, K.
D.; Luzzatti, L.; Biegel, A. A.: A new Ehlers-Danlos syndrome with
skeletal dysplasia. (Abstract) Am. J. Hum. Genet. 32: 118A, 1980.

18. Peltonen, L.; Kuivaniemi, H.; Palotie, A.; Horn, N.; Kaitila,
I.; Kivirikko, K. I.: Alterations in copper and collagen metabolism
in the Menkes syndrome and a new subtype of the Ehlers-Danlos syndrome. Biochemistry 22:
6156-6163, 1983.

19. Tang, J.; Robertson, S.; Lem, K. E.; Godwin, S. C.; Kaler, S.
G.: Functional copper transport explains neurologic sparing in occipital
horn syndrome. Genet. Med. 8: 711-718, 2006.

20. Tsukahara, M.; Imaizumi, K.; Kawai, S.; Kajii, T.: Occipital
horn syndrome: report of a patient and review of the literature. Clin.
Genet. 45: 32-35, 1994.

21. Vulpe, C.; Levinson, B.; Whitney, S.; Packman, S.; Gitschier,
J.: Isolation of a candidate gene for Menkes disease and evidence
that it encodes a copper-transporting ATPase. Nature Genet. 3: 7-13,
1993. Note: Erratum: Nature Genet. 3: 273 only, 1993.

22. Wakai, S.; Ishikawa, Y.; Nagaoka, M.; Okabe, M.; Minami, R.; Hayakawa,
T.: Central nervous system involvement and generalized muscular atrophy
in occipital horn syndrome: Ehlers-Danlos type IX--a first Japanese
case. J. Neurol. Sci. 116: 1-5, 1993.

*FIELD* CS
INHERITANCE:
X-linked recessive

HEAD AND NECK:
[Head];
Persistent, open anterior fontanel;
[Face];
Long, thin face;
High forehead;
Long philtrum;
[Nose];
Hooked nose;
[Mouth];
High-arched palate;
[Neck];
Long neck

CARDIOVASCULAR:
[Vascular];
Orthostatic hypotension;
Elongated, tortuous carotid arteries;
Intracranial arterial narrowing

CHEST:
[External features];
Narrow shoulders;
Narrow chest;
[Ribs, sternum, clavicles, and scapulae];
Short, broad clavicles;
Pectus excavatum;
Pectus carinatum;
Short, broad ribs

ABDOMEN:
[Gastrointestinal];
Chronic diarrhea;
Hiatal hernia

GENITOURINARY:
[Kidneys];
Hydronephrosis;
[Ureters];
Ureteral obstruction;
[Bladder];
Bladder diverticula;
Bladder rupture

SKELETAL:
Joint laxity;
Osteoporosis;
[Skull];
Occipital horn exostoses;
[Spine];
Kyphosis;
Mild platyspondyly;
[Pelvis];
Coxa valga;
Pelvic exostoses;
[Limbs];
Short humeri;
Genu valgum;
Limited elbow extension;
Limited knee extension;
[Hands];
Capitate-hamate fusion;
[Feet];
Pes planus

SKIN, NAILS, HAIR:
[Skin];
Soft skin;
Mildly extensible skin;
Loose, redundant skin;
Easy bruisability;
[Hair];
Coarse hair

NEUROLOGIC:
[Central nervous system];
Low-normal IQ

NEOPLASIA:
Bladder carcinoma

LABORATORY ABNORMALITIES:
Decreased serum copper;
Decreased ceruloplasmin

MOLECULAR BASIS:
Caused by mutation in the ATPase, Cu++ transporting, alpha polypeptide
gene (ATP7A, 300011.0002)

*FIELD* CN
Kelly A. Przylepa - revised: 10/24/2002

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 12/14/2006
joanna: 4/10/2003
joanna: 10/24/2002

*FIELD* CN
Ada Hamosh - updated: 7/25/2007
Anne M. Stumpf - updated: 5/23/2006
Moyra Smith - updated: 1/28/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
alopez: 08/08/2012
alopez: 1/31/2012
alopez: 1/26/2012
terry: 10/12/2010
carol: 3/12/2010
carol: 1/21/2010
terry: 8/26/2008
alopez: 7/31/2007
terry: 7/25/2007
carol: 3/15/2007
alopez: 5/23/2006
mgross: 11/10/1999
carol: 11/24/1998
mark: 1/29/1997
terry: 1/28/1997
jamie: 1/7/1997
jamie: 1/6/1997
mark: 2/8/1996
joanna: 2/4/1996
mark: 3/29/1995
pfoster: 4/22/1994
terry: 4/21/1994
warfield: 4/19/1994
mimadm: 4/18/1994
carol: 4/15/1994

MIM 309400
*RECORD*
*FIELD* NO
309400
*FIELD* TI
#309400 MENKES DISEASE
;;MK; MNK;;
MENKES SYNDROME;;
KINKY HAIR DISEASE;;
STEELY HAIR DISEASE;;
read moreCOPPER TRANSPORT DISEASE
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
Menkes disease is caused by mutation in the gene encoding
Cu(2+)-transporting ATPase, alpha polypeptide (ATP7A; 300011). The
occipital horn syndrome (304150) is caused by mutation in the same gene.

DESCRIPTION

Menkes disease is an X-linked recessive disorder characterized by
generalized copper deficiency. The clinical features result from the
dysfunction of several copper-dependent enzymes.

De Bie et al. (2007) provided a detailed review of the molecular
pathogenesis of Menkes disease.

CLINICAL FEATURES

In a family of English-Irish descent living in New York, Menkes et al.
(1962) described an X-linked recessive disorder characterized by early
retardation in growth, peculiar hair, and focal cerebral and cerebellar
degeneration. Severe neurologic impairment began within a month or two
of birth and progressed rapidly to decerebration. Five males were
affected but the gene could by inference be identified in 4 generations.
The failure to grow brought the affected infants to medical attention at
the age of a few weeks and death occurred in the first or second year of
life. The hair was stubby and white. Microscopically it showed twisting,
varying diameter along the length of the shaft, and often fractures of
the shaft at regular intervals. Rather extensive biochemical
investigations showed elevated plasma glutamic acid as the only
consistent abnormality. The anatomic change in the central nervous
system was described on the basis of 2 autopsies.

Bray (1965) observed 2 brothers who died as infants with spastic
dementia, seizures, and defective hair. Blood and urine amino acids were
normal. Whether this is the same disorder as that in Menkes' family was
unclear. The condition described by Yoshida et al. (1964) may have been
the same. French and Sherard (1967) presented evidence that they
interpreted as indicating that this disorder may represent an
abnormality of lipid metabolism. Their 16-month-old patient showed: (1)
scant, whitish, lackluster, kinky hair that microscopically showed pili
torti, monilethrix and trichorrhexis nodosa; (2) retarded growth; (3)
micrognathia and highly arched palate; (4) decline in mental
development; (5) onset of focal and generalized seizures; and (6)
spastic quadriparesis with clenched fists, opisthotonos, and scissoring.
Biochemical studies showed depressed serum tocopherol and normal amino
acid content of hair serum and urine. An abnormal autofluorescence is
displayed by hair and by Purkinje cells' axons.

'Kinky hair disease' proved a designation useful in detection of new
cases, since the hair change is an easily remembered feature by which
physicians can be alerted to the condition (O'Brien, 1968). Changes in
the metaphyses of the long bones and tortuosity of cerebral arteries
have been described. Hypothermia and acute illness with septicemia were
modes of presentation. Patchy abnormality of systemic arteries with
stenosis or obliteration was observed by Danks et al. (1971). They also
observed toluidine-blue-metachromasia of fibroblasts. Wesenberg et al.
(1969) pointed out that the fetal hair does not show pili torti.

Goka et al. (1976) found that cultured fibroblasts have a concentration
of copper over 5 times that of normal fibroblasts. Williams et al.
(1978) described the cellular pathology of Menkes disease.

Osaka et al. (1977) reported 2 Japanese families. They pointed out that
the hair may not be abnormal, that serum copper determination is a
simple and reliable diagnostic test, and that 'congenital hypocupraemia'
may be a preferred designation. An abnormality in egress of copper from
Menkes disease fibroblasts was suggested by studies of Chan et al.
(1978). Defective metallothionein (see 156530) was suggested.

Haas et al. (1981) reported an X-linked disorder of copper metabolism
which, by my interpretation, may be an allelic variant of Menkes
syndrome. The disorder affected 4 males in 3 sibships connected through
females. Similarities to Menkes disease were X-linked recessive
inheritance, marked psychomotor retardation with seizures, low serum
copper and ceruloplasmin (117700) levels, and a block in gut copper
absorption. Differences from Menkes disease included normal birth
weight, no hypothermia, grossly and microscopically normal hair, and
radiographically normal bones. Survivorship was much longer than in
Menkes disease. The neurologic disorder was static and characterized by
hypotonia and choreoathetosis.

Tonnesen et al. (1991) reviewed the cases of atypical Menkes reported by
Haas et al. (1981). No pili torti were found in one case and very few (2
in 1,000) in a second. In addition, low levels of copper and
ceruloplasmin in the serum were puzzling findings. However, (64)Cu
uptake and retention was significantly increased in the range seen for
classic Menkes patients, and copper uptake in female relatives gave the
same uptake pattern as in heterozygotes in other families with the
classic disorder.

Godwin-Austen et al. (1978) described a disorder clinically reminiscent
of Wilson disease but without Kayser-Fleischer rings. Symptoms began at
age 12 years and defective copper absorption from the distal intestine,
with high copper levels in rectal mucosa, was demonstrated. X-linked
inheritance was suggested.

Proud et al. (1996) reported on the clinical features of 4 affected
persons in 3 generations of a family that manifested an unusual variant
of the Menkes syndrome. These patients had normal head circumference,
moderate to severe mental retardation, onset at age of 3 to 4 years,
dysarthria, laxity of skin, bladder diverticula, tortuous vessels,
chronic diarrhea, and occipital exostoses (evident in 3 persons aged 18
to 38 years). Study of the MNK gene showed an A-to-T change at the +3
position of the splice donor site near the 3-prime end of the MNK coding
sequence resulting in abnormal splicing (Kaler et al., 1994). The
authors proposed that maintenance of 20% of normal splicing could
explain unique phenotypic manifestations in affected persons. Proud et
al. (1996) suggested that these patients, as well as a patient with
occipital horn syndrome reported by Wakai et al. (1993), represent a new
variant of Menkes syndrome. Phenotypic overlap between Menkes syndrome
and the occipital horn syndrome (304150) is to be expected since both
are caused by mutations in the ATP7A gene (300011).

Gerard-Blanluet et al. (2004) described occipital horns in a classic
case of Menkes disease caused by an 8-bp deletion in the ATP7A gene
(300011.0011). They pointed out that 'occipital horn' refers to a
wedge-shaped calcification that forms within the tendinous insertions of
the trapezius and sternocleidomastoid muscles at their attachment to the
occipital bone. They suggested that presence of voluntary traction on
these hyperlax tendons attached to the skull could then have provoked
calcification of the occipital tendons as an aberrant way of reparation.
Gerard-Blanluet et al. (2004) suggested that voluntary traction of the
relevant muscles persisting after 2 years of age, needing both sustained
voluntary head control and long survival, is required for the
development of occipital horns in patients with Menkes disease caused by
a deleterious mutation in the ATP7A gene.

Jankov et al. (1998) described a newborn male who presented with acute
onset of severe intraabdominal bleeding, hemorrhagic shock, and multiple
fractures leading to death on day 27. Menkes disease was diagnosed at
autopsy and confirmed by copper accumulation studies on cultured
fibroblasts. Such an early onset of fatal complications in Menkes
disease had not previously been reported. The mutation in this case was
said to have been identical to that found in an unrelated male with
Menkes disease who died at the age of 4 years without severe connective
tissue disease. Horn (1999) reported that the mutation in ATP7A was
arg980 to ter (300011.0005).

Tumer and Horn (1997) reviewed the clinical and genetic aspects of
Menkes syndrome, including phenotypic expression in females, mutation
spectrum, diagnosis, and treatment. They also discussed the mottled
mouse as a model for Menkes syndrome and new insights into normal and
defective copper metabolism provided by biochemical and genetic studies
of Menkes syndrome and Wilson disease (277900).

BIOCHEMICAL FEATURES

Danks et al. (1972) presented evidence of a defect in the intestinal
absorption of copper. Copper deficiency in animals leads to connective
tissue changes because formation of lysine-derived cross-links in
elastin and collagen is interfered with, the amine oxidase responsible
for the initial modification of lysine being copper-dependent. This may
explain the arterial abnormalities. The striking hair changes are
probably the result of defective formation of disulfide bonds in keratin
since this process is copper-dependent, and copper deficiency in sheep
leads to the formation of wool with defective cross-linking (Collie et
al., 1980). Menkes had sent hair from his original patients to the
Australian Wool Commission, but at that early date the Commission could
not identify the problem (Menkes, 1972).

Peltonen et al. (1983) found many similar abnormalities of copper and
collagen metabolism in the cultured fibroblasts of 13 patients with
Menkes syndrome and 2 patients with E-D IX. In both disorders,
fibroblasts had markedly increased copper content and rate of
incorporation of (64)Cu, and accumulation was in metallothionein (see
156350) or a metallothionein-like protein as previously established for
Menkes cells. Histochemical staining showed that copper was distributed
uniformly throughout the cytoplasm in both cell types, this location
being consistent with accumulation in metallothionein. Both fibroblast
types showed very low lysyl oxidase activity and increased
extractability of newly synthesized collagen, but no abnormality in cell
viability, duplication rate, prolyl 4-hydroxylase activity, or collagen
synthesis rate. Skin biopsy specimens from one E-D IX patient showed the
same abnormalities in lysyl oxidase activity and collagen
extractability. Fibroblasts of the mother of E-D IX patients showed
increased (64)Cu incorporation. The similarities in biochemical findings
between type IX Ehlers-Danlos syndrome and Menkes syndrome may indicate
allelism. In studies of cultured cells from both conditions, Kuivaniemi
et al. (1985) could not demonstrate that there was secreted into the
medium or contained in the cell any significant amounts of
copper-deficient, catalytically inactive lysyl oxidase protein. Although
the rapid degradation of a mutant protein could not be excluded, the
authors favored the idea that synthesis of the lysyl oxidase protein is
impaired.

Scheinberg and Collins (1989) suggested that the primary defect resides
in zinc, i.e., that Menkes disease is primarily a disorder of a putative
zinc-binding protein, which they symbolized ZBP, whose synthesis is
controlled by a gene on the X chromosome. When ionic zinc is present in
the liver or intestine it induces the synthesis of metallothionein to
which the zinc is bound. Since the affinity of metallothionein for
copper is 100,000 times greater than that for zinc, copper in either
organ displaces zinc and binds to metallothionein. In the liver such
bound copper is probably unavailable for incorporation into specific
copper 'apo' proteins. In the intestine copper does not enter the
circulation; advantage has been taken of this fact to decrease the
intestinal absorption of copper by administering zinc in Wilson disease
(277900). Deficiency of ZBP in Menkes disease would presumably result in
an increased concentration of nonprotein-bound, ionic zinc--the only
form of the element that has been shown to induce synthesis of
metallothionein.

OTHER FEATURES

Menkes (1988) gave a useful review in which he listed 6 cuproenzymes, 5
of which may account for features of the disorder: tyrosinase for
depigmentation of hair and skin pallor; lysyl oxidase for frayed and
split arterial intima (defect in elastin and collagen cross-linking);
monoamine oxidase for kinky hair; cytochrome c oxidase for hypothermia;
and ascorbate oxidase for skeletal demineralization.
Dopamine-beta-hydroxylase is also a cuproenzyme; what role its
deficiency may have in the phenotype of kinky hair disease is unclear.

CYTOGENETICS

Gerdes et al. (1990) described 3 patients with clinically and
biochemically typical Menkes syndrome; a chromosome abnormality was
found in only 1 (45X/46XX mosaicism). During a systematic chromosomal
survey of 167 unrelated boys with Menkes disease, Tumer et al. (1992)
found a unique rearrangement of the X chromosome involving an insertion
of the long arm segment Xq13.3-q21.2 into the short arm at band Xp11.4,
giving the karyotype 46,XY,ins(X)(p11.4q13.3q21.2). The same rearranged
X chromosome was present de novo in the boy's phenotypically normal
mother, where it was preferentially inactivated. RFLP and methylation
patterns at DXS255 indicated that the rearrangement originated from the
maternal grandfather. This finding supported localization of the MNK
locus to Xq13 and suggested fine mapping to subband Xq13.3. The
chromosomal band associated with the X-inactivation center (XIC; 314670)
was present, in this patient, on the proximal long arm of the rearranged
X chromosome, in line with the location of XIC proximal to MNK.

MAPPING

Wieacker et al. (1983) performed linkage studies in a large kindred with
Menkes syndrome using a cloned DNA sequence (RFLP), probe 1.28, that
maps to the proximal portion of Xp (between Xcen and Xp113). At least 2
crossovers and an estimated genetic distance of 16 cM were found (lod
score = 0.82). Horn et al. (1984) demonstrated linkage between Menkes
disease and a centromeric C-banding polymorphism. Other studies of
linkage with 2 RFLPs, MGU22 (which is close to the centromere) and L1.28
(which is in the Xp110-Xp113 segment), suggested that the Menkes locus
is distal to L1.28 (review by Ropers et al., 1983).

Wienker et al. (1983) suggested the following as the most likely gene
order: Xpter--MS--L1.28--MGU22. Comparative mapping suggested to Horn et
al. (1984) that the Menkes disease locus is on the long arm close to
band q13; on the mouse X-chromosome the homologous Mo locus ('mottled')
is located between the structural loci for phosphoglycerate kinase
(Pgk-1) and alpha-galactosidase (Ags), closely linked to the Pgk-1
locus, the human equivalent of which, PGK, has been assigned to Xq13.
Linkage studies in 5 Dutch families suggested close situation of the
Menkes locus and the centromere (recombination fraction 0.5, lod score
more than 3.0). Centromeric heteromorphism was used as the 'marker
trait.' There was probably no detectable linkage with Xg.

From a 3-point analysis, Tonnesen et al. (1986) concluded that the
Menkes locus is on the long arm of the X chromosome proximal to DXYS1.
In studies of 4 families in which a characteristic X-centromeric marker
was segregating with Menkes disease, Friedrich et al. (1983) found only
1 recombinant out of 18 opportunities, indicating that the gene is near
the centromere on either the long arm or the short arm. Kapur et al.
(1987) suggested that the Menkes syndrome gene may lie in the Xq13 band
because of the finding of Menkes syndrome in a female with a de novo
balanced translocation t(2;X). The breakpoint in the X chromosome was at
Xq13.1.

Verga et al. (1991) refined the localization of the MNK locus. They
established a lymphoblastoid cell line from the patient of Kapur et al.
(1987) and used it to isolate the der(2) translocation chromosome in
human/hamster somatic cell hybrids. Southern blot analyses using a
number of probes specific for chromosomes X and 2 showed that the
breakpoint in this patient--and, therefore, probably the Menkes
gene--mapped to a small subregion of band Xq13.2-q13.3 proximal to the
PGK1 (311800) locus and distal to all other Xq13 loci tested. Hershon
(1988) concluded from study of an X/A translocation that the locus lies
near the boundary between Xq12 and Xq13, probably at Xq13.1.

Tonnesen et al. (1992) reported on linkage analyses in 11 families in
which more than one affected patient had been found. They concluded that
the most likely location of MNK is Xq12-q13.3. Working with DNA from the
cells from the patient with the translocation t(2;X) reported by Kapur
et al. (1987), Consalez et al. (1992) developed a cosmid contig
extending 150 kb from a nearby CpG island across the breakpoint on the X
chromosome (see erratum indicating additional information on the
location of the translocation breakpoint).

Sugio et al. (1998) described a Japanese girl with Menkes disease due to
a de novo X;21 reciprocal translocation in which a breakpoint at Xq13.3
had disrupted the ATP7A gene. They demonstrated that the normal X
chromosome was late replicating, whereas the derivative X chromosome was
selectively early replicating.

Abusaad et al. (1999) reported a female with typical manifestations of
Menkes disease who carried a de novo balanced translocation
46,X,t(X;13)(q13.3;q14.3). The diagnosis was confirmed by findings of
low levels of serum copper and ceruloplasmin with increased copper
uptake in cultured fibroblasts. The authors hypothesized that function
of the ATP7A gene had been disrupted by the translocation, either by a
structural disruption or by 'silencing' as a result of inappropriate
localized inactivation in an otherwise active X;13 derivative
chromosome.

MOLECULAR GENETICS

Three independent groups, in San Francisco (Vulpe et al., 1993), Oxford
(Chelly et al., 1993), and Michigan (Mercer et al., 1993), cloned a
candidate gene for Menkes disease. Vulpe et al. (1993), who proceeded
directly from the translocation breakpoints at Xq13.3 to the gene by
cDNA library screening with a YAC fragment and exon trapping
experiments, succeeded in obtaining a complete set of clones
corresponding to an 8.5-kb transcript that encodes a 1,500 amino acid
protein. The 5-prime region of the same locus was also obtained by
Chelly et al. (1993) who took the more cumbersome but genetically
rigorous step of first identifying genomic fragments that were deleted
in cytogenetically normal patients with Menkes disease, and by Mercer et
al. (1993) who employed a strategy involving long range restriction
mapping and fluorescence in situ hybridization (FISH) analysis. Two
lines of evidence strongly implicated the cloned MNK locus in the
etiogenesis of Menkes disease: nonoverlapping portions of the gene were
deleted in 16 of 100 unrelated patients (Chelly et al., 1993), and the
expression of the transcript was reduced or altered in 23 of 32 patients
(Vulpe et al., 1993; Mercer et al., 1993). By a database search of the
predicted sequence, Vulpe et al. (1993) found strong homology to P-type
ATPases, a family of integral membrane proteins that use an aspartyl
phosphate intermediate to transport cations across membranes. The
protein has the characteristics of a copper binding protein. Northern
blot experiments showed that MNK mRNA is present in a variety of cell
types and tissues except liver, in which expression is reduced or
absent. This is consistent with the clinical observation that the liver
is largely unaffected in Menkes disease and fails to accumulate excess
copper.

The MNK protein is localized to the trans-Golgi network (TGN) (Petris et
al., 1996). Studies with copper-resistant Chinese hamster ovary cells
(CHO) by Petris et al. (1996) suggested that the MNK protein cycles
between the TGN and the plasma membrane, depending on the concentration
of copper within the cell. TGN38 (603062) is another protein that cycles
between the TGN and the plasma membrane (Ladinsky and Howell, 1992;
Reaves et al., 1993). A number of Golgi-resident proteins contain
specific localization signals, and Francis et al. (1998) showed that
this is true also of MNK. By immunofluorescence, they showed that the
full-length recombinant Menkes protein, the isoform that is not
expressed in the occipital horn syndrome, localizes to the Golgi
apparatus, whereas the alternatively spliced form, which lacks sequences
for transmembrane domains 3 and 4 encoded by exon 10 and is expressed in
the occipital horn syndrome, localizes to the endoplasmic reticulum.
Using sequences from exon 10 fused to a non-Golgi reporter molecule,
Francis et al. (1998) showed that a 38-amino acid sequence containing
transmembrane domain 3 of the MNK protein was sufficient for
localization to the Golgi complex. Therefore, the protein sequence
encoded by exon 10 may be responsible for this differential localization
and both isoforms may be required for comprehensive transport of copper
within the cell. By immunogold electron microscopic analyses, La
Fontaine et al. (1998) mapped the MNK protein to the TGN. When the
extracellular copper concentration was increased, MNK in the CHO cells
was redistributed to the cytoplasm and plasma membrane, but returned to
the TGN under basal, low copper conditions.

The MNK protein is normally localized predominantly in the TGN; however,
when cells are exposed to excessive copper it is rapidly relocalized to
the plasma membrane where it functions in copper efflux. Petris and
Mercer (1999) found that in cells stably expressing tagged MNK protein,
extracellular antibodies were internalized to the perinuclear region,
indicating that the tagged MNK at the TGN constitutively cycles via the
plasma membrane in basal copper conditions. Under elevated copper
conditions, the tagged MNK was recruited to the plasma membrane;
however, internalization of the tagged protein was not inhibited, and
the protein continued to recycle through cytoplasmic membrane
compartments. These findings suggested that copper stimulates exocytic
movement of MNK to the plasma membrane rather than reducing MNK
retrieval and indicated that MNK may remove copper from the cytoplasm by
transporting copper into the vesicles through which it cycles.

Screening 383 unrelated patients affected with Menkes syndrome, Tumer et
al. (2003) found 57 with gross deletions in the ATP7A gene (14.9%).
Except for a few cases, gross gene deletions resulted in a classic form
of Menkes disease with death in early childhood.

Moller et al. (2005) identified 21 novel missense mutations in the ATP7A
gene in patients with Menkes disease. The mutations were located within
the conserved part of ATP7A between residues val842 and ser1404.
Molecular 3-dimensional modeling based on the structure of ATP2A1
(108730) showed that the mutations were more spatially clustered than
expected from the primary sequence. The authors suggested that some of
the mutations may interfere with copper binding.

DIAGNOSIS

Carrier status for the Menkes disease gene can usually be determined by
examination of multiple hairs from scattered scalp sites for pili torti.
Carrier status can, of course, never be completely excluded by negative
findings of such scrutiny. Moore and Howell (1985) found pili torti in
all affected males and in 43% of 28 obligate carriers or females at
risk. When present, pili torti can be considered, in their opinion, a
reliable indicator of heterozygosity. Changes in the metaphyses of the
long bones resemble scurvy. Ascorbic acid oxidase is copper-dependent.
Tumer et al. (1994) described first trimester prenatal diagnosis of
Menkes disease using a specific DNA probe.

CLINICAL MANAGEMENT

Williams et al. (1977) discussed studies of metabolism and long-term
copper therapy in Menkes disease. Sander et al. (1988) described a
patient who survived to the age of 13.5 years. Most patients have died
between the ages of 6 months and 3 years. The administration of copper
may have helped in the survival. In studies by De Groot et al. (1989),
vitamin C therapy was ineffective. Procopis et al. (1981) described a
mild, presumably allelic form. They urged that mentally retarded or
ataxic boys with pili torti be investigated with this disorder in mind.
Westman et al. (1988) described a second child with the atypical form
who had survived to age 9 years and was doing well clinically. Danks
(1988) reported on the progress of the patient reported by Procopis et
al. (1981). By then aged 10 years, the patient had been treated for many
years with injections of copper histidinate. Ataxia and dysarthria had
been the principal problems. No radiologic abnormalities had developed
in the skull or limb bones; in particular, no 'occipital horn' was
discerned.

Sherwood et al. (1989) found excellent results from subcutaneous copper
histidinate therapy in 2 unrelated boys with classic Menkes disease.
Copper histidinate is probably the form in which copper crosses the
blood-brain barrier (Hartter and Barnea, 1988). One of the patients
developed orthostatic hypotension such that he preferred to crouch
rather than stand. The other patient had 2 massive bladder diverticula.

Whereas parentally administered copper in the form of copper sulfate or
copper-EDTA probably does not produce a substantial clinical
improvement, Tumer et al. (1996) found evidence for the efficacy of
copper-histidine, which is naturally present in the serum and is
quantitatively important in copper transport. Copper-histidine appeared
to be ineffective when it was given after the first few months of life.
However, in 2 unrelated patients with this disorder who were born
prematurely and received early copper-histidine treatment, the response
was favorable (see Sherwood et al. (1989) and Sarkar et al. (1993)). At
the time of the Tumer et al. (1996) report, these patients were aged 19
and 9 years and presented with a milder clinical course, mainly
characterized by connective tissue abnormalities resembling the
occipital horn syndrome (304150). An unresolved question concerned the
severity of the disease in each case. One of the patients had a positive
family history suggesting that he was liable to the severe form, but the
possibility of intrafamilial clinical variation could not be excluded.
To clarify these questions, Tumer et al. (1996) characterized the
genetic defects in the ATP7A gene. Using a combination of single-strand
conformation analysis and direct sequencing of amplified exons, they
detected a single bp deletion in exon 4 in one patient and in exon 12 in
the other. Both mutations led to a frameshift and created a premature
termination codon within the same exon. RT-PCR analysis of total
fibroblast RNA of both patients showed no evidence of exon skipping,
indicating that the mutation resulted in severely truncated proteins.
They concluded that the disorder would be expected to be severe and that
the therapy had been effective. A newspaper photograph of the 9-year-old
patient indicated his appearance at the time of the report.

Christodoulou et al. (1998) described the long-term clinical course of 4
boys who had Menkes disease treated from early infancy with parenteral
copper-histidine, with follow-up over 10 to 20 years. Male relatives of
3 of the 4 had a severe clinical course compatible with classic Menkes
disease. As a consequence of early treatment, their patients had normal
or near-normal intellectual development, but developed many of the more
severe somatic abnormalities of the related disorder occipital horn
syndrome, including severe orthostatic hypotension in 2. In addition, 1
boy developed a previously unreported anomaly: massive splenomegaly and
hypersplenism as a consequence of a splenic artery aneurysm. The oldest
patient was 20 years of age at the time of report. Hypotension had been
a problem from the age of 14 years. A syncopal episode on standing was
associated with bradycardia. Treatment with atropine resulted in a brisk
increase in heart rate and rapid clinical recovery. There was no
increase in blood pressure following immersion of the hand in ice-cold
water, or following a mental arithmetic challenge, suggesting that his
postural hypotension may have an autonomic basis. It was subsequently
treated with a peripheral alpha-adrenergic agonist, midodrine, in
combination with fludrocortisone. He suffered from persistent chronic
diarrhea since early infancy.

Kanumakala et al. (2002) evaluated the bone mineral density (BMD)
changes following pamidronate treatment in children with Menkes disease.
Three children with Menkes disease and significant osteoporosis with or
without pathologic fractures all received pamidronate treatment for 1
year. There were 34 to 55% and 16 to 36% increases in lumbar spine bone
mineral content and areal bone mineral density, respectively, following
1 year of treatment with pamidronate. There were no further fractures in
2 of the 3 children treated. No adverse effects of pamidronate treatment
were noted. Kanumakala et al. (2002) suggested that pamidronate may be
an effective treatment modality for the management of osteoporosis in
children with Menkes disease.

Olivares et al. (2006) reported a 9-year-old boy with Menkes disease who
had been treated with subcutaneous copper-histidine since age 12 months.
Although treatment did not prevent severe growth and mental retardation,
it normalized plasma levels of copper and ceruloplasmin, improved his
muscular tone, motor activity, and irritability, and most importantly,
he never developed seizures. The patient had a missense mutation in the
ATP7A gene, which the authors hypothesized may have resulted in better
response to therapy than a more deleterious mutation.

POPULATION GENETICS

Danks et al. (1971) suggested that the frequency may be 1 in 40,000 live
births in Melbourne and higher than previously thought because some
patients may die undiagnosed.

Tonnesen et al. (1991) estimated that the combined frequency of
live-born Menkes disease patients in Denmark, France, the Netherlands,
the United Kingdom, and West Germany was 1 per 298,000 live-born babies
in the period 1976 to 1987. They estimated the mutation rate for Menkes
disease to be 1.96 x 10(-6), based on the number of isolated Menkes
cases born during that period.

ANIMAL MODEL

The mottled series of mutations in the mouse may be homologous to Menkes
syndrome (Hunt, 1974). The 'mottled' mutation in the hamster is also
probably homologous (Yoon, 1973). Brophy et al. (1988) studied aortic
aneurysm in the 'blotchy' mouse, one of the mottled series of mutations.
Affected animals had a progressive increase in the instance of aneurysms
with age, reaching 100% within 6 months. Most aneurysms occurred in the
ascending aorta, with some also present in the descending thoracic and
abdominal segments. Some animals had multiple aneurysms.

George et al. (1994) analyzed mouse Mnk, a murine locus homologous to
Menkes disease, in both normal mice and those with the mottled
phenotype.

Male mice with the Mottled-Brindled allele accumulate copper in the
intestine, fail to export copper to peripheral organs, and die a few
weeks after birth. Much of the intestinal copper found in
Mottled-Brindled mice is bound by metallothionein (MT); see 156350. To
determine the function of MT in the presence of Atp7a deficiency, Kelly
and Palmiter (1996) crossed Mottled-Brindled females with males that
bear a targeted disruption of the Mt1 and Mt2 genes. On the
metallothionein-deficient background most Mottled males as well as
heterozygous Mottled females died before embryonic day 11. The authors
explained the lethality in females by preferential inactivation of the
paternal X chromosome in extra embryonic tissues and resultant copper
toxicity in the absence of MT. In support of this hypothesis, Kelly and
Palmiter (1996) found that cell lines derived from metallothionein
deficient, Mottled embryos were very sensitive to copper toxicity. They
concluded that MT is essential to protect against copper toxicity in
embryonic placenta, providing a second line of defense when copper
effluxers are defective. They also stated that MT probably protects
against hepatic copper toxicity in Wilson disease and the LEC rat model
in which a similar copper effluxer, ATP7B (606882), is defective,
because MT accumulates to high levels in the liver in those diseases.

The nature of the mutation in the brindled mouse is of importance in
understanding the normal role of the protein encoded by ATP7A and for
devising treatment strategies for Menkes disease. Grimes et al. (1997)
showed that the brindled mouse has a deletion of 2 amino acids in a
highly conserved, but functionally uncharacterized, region of the Atp7a
gene. They also presented Western blot data for the normal gene product
in tissues. In the kidney, immunohistochemistry demonstrated the protein
in proximal and distal tubules, with a distribution identical in mutant
and normal mice. This distribution was considered consistent with the
protein being involved in copper resorption from the urine.

Masson et al. (1997) studied copper uptake and retention in fibroblast
cultures established from 4 independent mottled alleles associated with
postnatal male survival, 5 independent mottled alleles associated with
prenatal death of affected males, and 12 controls. Both groups of
mutants were separable from controls on both copper uptake and copper
retention assays. Values obtained were the same as those previously
reported for human fibroblasts established from patients with Menkes
disease, but no significant differences were found between the alleles
associated with survival and those associated with prenatal death.

*FIELD* SA
Barnard et al. (1978); Billings and Degnan (1971); Bucknall et al.
(1973); Camakaris et al. (1980); Collie et al. (1978); Daish et al.
(1978); Danks and Cartwright (1973); Danks et al. (1972); Garnica
et al. (1977); Grover and Scrutton (1975); Hara et al. (1979); Harcke
et al. (1977); Horn (1983); Horn (1981); Horn (1980); Horn (1976);
Horn et al. (1978); Horn et al. (1980); Iwata et al. (1979); Leone
et al. (1985); McKusick (1972); Prohaska and Lukasewycz (1981); Rowe
et al. (1974); Royce et al. (1980); Tonnesen et al. (1985); Tonnesen
et al. (1991)
*FIELD* RF
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1999.

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4. Bray, P. F.: Sex-linked neurodegenerative disease associated with
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5. Brophy, C. M.; Tilson, J. E.; Braverman, I. M.; Tilson, M. D.:
Age of onset, pattern of distribution, and histology of aneurysm development
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1988.

6. Bucknall, W. E.; Haslam, R. H. A.; Holtzman, N. A.: Kinky hair
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P.; Cotton, R. G. H.: Altered copper metabolism in cultured cells
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8. Chan, W.-Y.; Garnica, A. D.; Rennert, O. M.: Cell culture studies
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9. Chelly, J.; Tumer, Z.; Tonnesen, T.; Petterson, A.; Ishikawa-Brush,
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protein. Nature Genet. 3: 14-19, 1993.

10. Christodoulou, J.; Danks, D. M.; Sarkar, B.; Baerlocher, K. E.;
Casey, R.; Horn, N.; Tumer, Z.; Clarke, J. T. R.: Early treatment
of Menkes disease with parenteral cooper (sic)-histidine: long-term
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1998.

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12. Collie, W. R.; Moore, C. M.; Goka, T. J.; Howell, R. R.: Pili
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13. Consalez, G. G.; Gecz, J.; Stayton, C. L.; Dabovic, B.; Pasini,
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18. Danks, D. M.; Cartwright, E.; Campbell, P. E.; Mayne, V.: Is
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22. Francis, M. J.; Jones, E. E.; Levy, E. R.; Ponnambalam, S.; Chelly,
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25. Garnica, A. D.; Frias, J. L.; Rennert, O. M.: Menkes kinky hair
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26. George, A. M.; Reed, V.; Glenister, P.; Chelly, J.; Tumer, Z.;
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35. Harcke, H. T.; Capitanio, M. A.; Grover, W. D.; Valdes-Dapena,
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36. Hartter, D. E.; Barnea, A.: Brain tissue accumulates (64)copper
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37. Hershon, K.: Personal Communication. New York, N. Y. 10/13/1988.

38. Horn, N.: Menkes' X-linked disease: prenatal diagnosis and carrier
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39. Horn, N.: Personal Communication. Copenhagen, Denmark 2/25/1999.

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41. Horn, N.: Menkes X-linked disease: heterozygous phenotype in
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42. Horn, N.: Copper incorporation studies on cultured cells for
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43. Horn, N.; Heydorn, K.; Damsgaard, E.; Tygstrup, I.; Vestermark,
S.: Is Menkes syndrome a copper storage disorder? Clin. Genet. 14:
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44. Horn, N.; Mooy, P.; McGuire, V. M.: Menkes X linked disease:
two clonal cell populations in heterozygotes. J. Med. Genet. 17:
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45. Horn, N.; Stene, J.; Mollekaer, A.-M.; Friedrich, U.: Linkage
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46. Hunt, D. M.: Primary defect in copper transport underlies mottled
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47. Iwata, M.; Hirano, A.; French, J. H.: Degeneration of the cerebellar
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48. Jankov, R. P.; Boerkoel, C. F.; Hellmann, J.; Sirkin, W. L.; Tumer,
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49. Kaler, S. G.; Gallo, L. K.; Proud, V. K.; Percy, A. K.; Mark,
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54. Ladinsky, M. S.; Howell, K. E.: The trans-Golgi network can be
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55. La Fontaine, S.; Firth, S. D.; Lockhart, P. J.; Brooks, H.; Parton,
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56. Leone, A.; Pavlakis, G. N.; Hamer, D. H.: Menkes' disease: abnormal
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57. Masson, W.; Hughes, H.; Papworth, D.; Boyd, Y.; Horn, N.: Abnormalities
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58. McKusick, V. A.: Heritable Disorders of Connective Tissue.
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59. Menkes, J. H.: Kinky hair disease. Pediatrics 50: 181-182,
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62. Mercer, J. F. B.; Livingston, J.; Hall, B.; Paynter, J. A.; Begy,
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disease by positional cloning. Nature Genet. 3: 20-25, 1993.

63. Moller, L. B.; Bukrinsky, J. T.; Molgaard, A.; Paulsen, M.; Lund,
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part of ATP7A. Hum. Mutat. 26: 84-93, 2005.

64. Moore, C. M.; Howell, R. R.: Ectodermal manifestations in Menkes
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65. O'Brien, J. S.: Personal Communication. Los Angeles, Calif.
1968.

66. Olivares, J. L.; Bueno, I.; Gallati, S.; Ramos, F. J.: Late-onset
treatment in Menkes disease: is there a correlation between genotype
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67. Osaka, K.; Sato, N.; Matsumoto, S.; Ogino, H.; Kadama, S.; Yokoyama,
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62-68, 1977.

68. Peltonen, L.; Kuivaniemi, H.; Palotie, A.; Horn, N.; Kaitila,
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6156-6163, 1983.

69. Petris, M. J.; Mercer, J. F.; Culvenor, J. G.; Lockhart, P.; Gleeson,
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70. Petris, M. J.; Mercer, J. F. B.: The Menkes protein (ATP7A; MNK)
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71. Procopis, P.; Camakaris, J.; Danks, D. M.: A mild form of Menkes
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72. Prohaska, J. R.; Lukasewycz, O. A.: Copper deficiency suppresses
the immune response of mice. Science 213: 559-561, 1981.

73. Proud, V. K.; Mussell, H. G.; Kaler, S. G.; Young, D. W.; Percy,
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of natural history and clinical phenotype. Am. J. Med. Genet. 65:
44-51, 1996.

74. Reaves, B.; Horn, M.; Banting, G.: TGN38/41 recycles between
the cell surface and the TGN: brefeldin A affects its rate of return
to the TGN. Mol. Biol. Cell 4: 93-105, 1993.

75. Ropers, H.-H.; Wieacker, P.; Wienker, T. F.; Davies, K.; Williamson,
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76. Rowe, D. W.; McGoodwin, E. B.; Martin, G. R.; Sussman, M. D.;
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77. Royce, P. M.; Camakaris, J.; Danks, D. M.: Reduced lysyl oxidase
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78. Sander, C.; Niederhoff, H.; Horn, N.: Life-span and Menkes kinky
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79. Sarkar, B.; Ligertat-Walsh, K.; Clarke, J. T. R.: Copper-histidine
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80. Scheinberg, I. H.; Collins, J. C.: Menkes' disease: a disorder
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81. Sherwood, G.; Sarkar, B.; Sass Kortsak, A.: Copper histidinate
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82. Sugio, Y.; Sugio, Y.; Kuwano, A.; Miyoshi, O.; Yamada, K.; Niikawa,
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*FIELD* CS
INHERITANCE:
X-linked recessive

GROWTH:
[Height];
Short stature;
[Other];
Intrauterine growth retardation

HEAD AND NECK:
[Head];
Microcephaly;
Brachycephaly;
Wormian bones;
[Face];
Pudgy cheeks

CARDIOVASCULAR:
[Vascular];
Intracranial hemorrhage

SKELETAL:
Osteoporosis;
Joint laxity;
[Skull];
Wormian bones;
[Limbs];
Metaphyseal widening with spurs

SKIN, NAILS, HAIR:
[Skin];
Hypopigmentation;
Skin laxity;
[Hair];
Steely, kinky, sparse hair;
Twisted and partial breaks on magnification

NEUROLOGIC:
[Central nervous system];
Neurologic degeneration;
Hypertonia;
Mental retardation;
Seizures;
Intracranial hemorrhage;
Hypothermia

LABORATORY ABNORMALITIES:
Low copper and ceruloplasmin

MISCELLANEOUS:
Classic severe form shows onset at 2 to 3 months of age;
Early death (usually by 3 years of age);
A milder form has also been reported;
Female carriers may have subtle manifestations;
Incidence ranges from 1 in 40,000 to 1 in 350,000 births

MOLECULAR BASIS:
Caused by mutation in the ATPase, Cu++ transporting, alpha polypeptide
gene (ATP7A, 300011.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 07/21/2011
Cassandra L. Kniffin - updated: 1/2/2008
Michael J. Wright - revised: 6/22/1999
Ada Hamosh - revised: 6/22/1999

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
ckniffin: 07/21/2011
joanna: 3/19/2008
ckniffin: 1/2/2008
joanna: 3/14/2005
joanna: 5/7/2002
root: 6/24/1999
kayiaros: 6/22/1999

*FIELD* CN
Cassandra L. Kniffin - updated: 1/2/2008
Cassandra L. Kniffin - updated: 8/22/2006
Cassandra L. Kniffin - updated: 6/2/2006
Victor A. McKusick - updated: 11/23/2004
Victor A. McKusick - updated: 1/12/2004
Ada Hamosh - updated: 10/7/2003
Sonja A. Rasmussen - updated: 1/10/2000
Victor A. McKusick - updated: 10/25/1999
Victor A. McKusick - updated: 3/12/1999
Victor A. McKusick - updated: 2/24/1999
Victor A. McKusick - updated: 12/21/1998
Victor A. McKusick - updated: 8/6/1998
Victor A. McKusick - updated: 3/27/1998
Michael J. Wright - updated: 2/11/1998
Clair A. Francomano - updated: 2/10/1998
Victor A. McKusick - updated: 8/15/1997
Iosif W. Lurie - updated: 1/6/1997
Mark H. Paalman - updated: 6/2/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 11/29/2012
terry: 11/28/2012
alopez: 8/8/2012
carol: 5/6/2010
terry: 3/31/2009
terry: 8/27/2008
wwang: 1/15/2008
ckniffin: 1/2/2008
wwang: 11/30/2007
wwang: 8/22/2006
wwang: 6/6/2006
ckniffin: 6/2/2006
alopez: 3/15/2006
ckniffin: 3/17/2005
tkritzer: 11/30/2004
terry: 11/23/2004
cwells: 1/15/2004
terry: 1/12/2004
cwells: 10/7/2003
carol: 2/27/2003
carol: 4/29/2002
carol: 12/26/2000
mgross: 1/10/2000
mgross: 11/10/1999
mgross: 11/5/1999
terry: 10/25/1999
kayiaros: 7/12/1999
terry: 3/12/1999
carol: 3/7/1999
terry: 2/24/1999
carol: 12/29/1998
terry: 12/21/1998
psherman: 10/21/1998
carol: 9/25/1998
terry: 8/19/1998
carol: 8/7/1998
terry: 8/6/1998
carol: 4/7/1998
carol: 4/6/1998
joanna: 3/27/1998
alopez: 2/18/1998
mark: 2/12/1998
mark: 2/10/1998
jenny: 8/19/1997
terry: 8/15/1997
alopez: 7/29/1997
alopez: 7/8/1997
carol: 6/20/1997
jamie: 1/7/1997
jamie: 1/6/1997
joanna: 8/12/1996
mark: 7/22/1996
mark: 6/2/1996
terry: 3/26/1996
joanna: 2/4/1996
mark: 1/8/1996
terry: 1/4/1996
pfoster: 11/14/1995
mark: 6/11/1995
terry: 2/22/1995
carol: 11/7/1994
davew: 8/22/1994
warfield: 4/20/1994

RBCC Red Blood Cell Collection

Full text data of ATP7A