Full text data of MTAP
MTAP
(MSAP)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
S-methyl-5'-thioadenosine phosphorylase; 2.4.2.28 (5'-methylthioadenosine phosphorylase; MTA phosphorylase; MTAP; MTAPase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
S-methyl-5'-thioadenosine phosphorylase; 2.4.2.28 (5'-methylthioadenosine phosphorylase; MTA phosphorylase; MTAP; MTAPase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00011876
IPI00011876 S-methyl-5-thioadenosine phosphorylase Plays a major role in polyamine metabolism and is important for the salvage of both adenine and methionine. soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a not mentioned n/a found at its expected molecular weight found at molecular weight
IPI00011876 S-methyl-5-thioadenosine phosphorylase Plays a major role in polyamine metabolism and is important for the salvage of both adenine and methionine. soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a not mentioned n/a found at its expected molecular weight found at molecular weight
UniProt
Q13126
ID MTAP_HUMAN Reviewed; 283 AA.
AC Q13126; I2G7M5; I2G7M6; I2G7M7; I2G7M8; I2G7M9; I2G7N0; Q5T3P3;
read moreAC Q9H010;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 03-APR-2007, sequence version 2.
DT 22-JAN-2014, entry version 145.
DE RecName: Full=S-methyl-5'-thioadenosine phosphorylase;
DE EC=2.4.2.28;
DE AltName: Full=5'-methylthioadenosine phosphorylase;
DE Short=MTA phosphorylase;
DE Short=MTAP;
DE Short=MTAPase;
GN Name=MTAP; Synonyms=MSAP;
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], AND VARIANT ILE-56.
RC TISSUE=Epidermis;
RX PubMed=7604019; DOI=10.1073/pnas.92.14.6489;
RA Olopade O.I., Pomykala H.M., Hagos F., Sveen L.W., Espinosa R. III,
RA Dreyling M.H., Gursky S., Stadler W.M., le Beau M.M., Bohlander S.K.;
RT "Construction of a 2.8-megabase yeast artificial chromosome contig and
RT cloning of the human methylthioadenosine phosphorylase gene from the
RT tumor suppressor region on 9p21.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:6489-6493(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RC TISSUE=Placenta;
RX PubMed=8650244; DOI=10.1073/pnas.93.12.6203;
RA Nobori T., Takabayashi K., Tran P., Orvis L., Batova A., Yu A.L.,
RA Carson D.A.;
RT "Genomic cloning of methylthioadenosine phosphorylase: a purine
RT metabolic enzyme deficient in multiple different cancers.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:6203-6208(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 3; 4; 5; 6 AND 7), AND
RP INVOLVEMENT IN DMSMFH.
RX PubMed=22464254; DOI=10.1016/j.ajhg.2012.02.024;
RA Camacho-Vanegas O., Camacho S.C., Till J., Miranda-Lorenzo I.,
RA Terzo E., Ramirez M.C., Schramm V., Cordovano G., Watts G., Mehta S.,
RA Kimonis V., Hoch B., Philibert K.D., Raabe C.A., Bishop D.F.,
RA Glucksman M.J., Martignetti J.A.;
RT "Primate genome gain and loss: a bone dysplasia, muscular dystrophy,
RT and bone cancer syndrome resulting from mutated retroviral-derived
RT MTAP transcripts.";
RL Am. J. Hum. Genet. 90:614-627(2012).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ILE-56.
RC TISSUE=Colon;
RA Li Q., Cao W.-X., Zhang Y., Shi M.-M., Liu B.-Y., Zhu Z.-G.,
RA Lin Y.-Z.;
RT "Identification of human methylthioadenosine phosphorylase (MTAP) mRNA
RT mutation in colon cancer cell line COLO 205.";
RL Submitted (AUG-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [6]
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ILE-56.
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, AND SUBUNIT.
RX PubMed=3091600;
RA Della Ragione F., Carteni-Farina M., Gragnaniello V., Schettino M.I.,
RA Zappia V.;
RT "Purification and characterization of 5'-deoxy-5'-methylthioadenosine
RT phosphorylase from human placenta.";
RL J. Biol. Chem. 261:12324-12329(1986).
RN [9]
RP BIOPHYSICOCHEMICAL PROPERTIES, AND SUBUNIT.
RX PubMed=8687427; DOI=10.1006/bbrc.1996.0926;
RA Ragione F.D., Takabayashi K., Mastropietro S., Mercurio C., Oliva A.,
RA Russo G.L., Pietra V.D., Borriello A., Nobori T., Carson D.A.,
RA Zappia V.;
RT "Purification and characterization of recombinant human 5'-
RT methylthioadenosine phosphorylase: definite identification of coding
RT cDNA.";
RL Biochem. Biophys. Res. Commun. 223:514-519(1996).
RN [10]
RP INVOLVEMENT IN OSTEOSARCOMA.
RX PubMed=11895909;
RA Garcia-Castellano J.M., Villanueva A., Healey J.H., Sowers R.,
RA Cordon-Cardo C., Huvos A., Bertino J.R., Meyers P., Gorlick R.;
RT "Methylthioadenosine phosphorylase gene deletions are common in
RT osteosarcoma.";
RL Clin. Cancer Res. 8:782-787(2002).
RN [11]
RP INVOLVEMENT IN OSTEOSARCOMA.
RX PubMed=17912432;
RA Miyazaki S., Nishioka J., Shiraishi T., Matsumine A., Uchida A.,
RA Nobori T.;
RT "Methylthioadenosine phosphorylase deficiency in Japanese osteosarcoma
RT patients.";
RL Int. J. Oncol. 31:1069-1076(2007).
RN [12]
RP INVOLVEMENT IN MALIGNANT MELANOMA.
RX PubMed=19097084; DOI=10.1002/jcb.21984;
RA Stevens A.P., Spangler B., Wallner S., Kreutz M., Dettmer K.,
RA Oefner P.J., Bosserhoff A.K.;
RT "Direct and tumor microenvironment mediated influences of 5'-deoxy-5'-
RT (methylthio)adenosine on tumor progression of malignant melanoma.";
RL J. Cell. Biochem. 106:210-219(2009).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [14]
RP INVOLVEMENT IN GASTRIC CANCER.
RX PubMed=21412930; DOI=10.1002/gcc.20867;
RA Kim J., Kim M.A., Min S.Y., Jee C.D., Lee H.E., Kim W.H.;
RT "Downregulation of methylthioadenosine phosphorylase by homozygous
RT deletion in gastric carcinoma.";
RL Genes Chromosomes Cancer 50:421-433(2011).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) IN COMPLEX WITH MTA.
RX PubMed=10404592; DOI=10.1016/S0969-2126(99)80084-7;
RA Appleby T.C., Erion M.D., Ealick S.E.;
RT "The structure of human 5'-deoxy-5'-methylthioadenosine phosphorylase
RT at 1.7-A resolution provides insights into substrate binding and
RT catalysis.";
RL Structure 7:629-641(1999).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.03 ANGSTROMS) IN COMPLEX WITH SUBSTRATE
RP ANALOGS.
RX PubMed=15122881; DOI=10.1021/bi035492h;
RA Lee J.E., Settembre E.C., Cornell K.A., Riscoe M.K., Sufrin J.R.,
RA Ealick S.E., Howell P.L.;
RT "Structural comparison of MTA phosphorylase and MTA/AdoHcy
RT nucleosidase explains substrate preferences and identifies regions
RT exploitable for inhibitor design.";
RL Biochemistry 43:5159-5169(2004).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) IN COMPLEX WITH INHIBITORS.
RX PubMed=14705926; DOI=10.1021/bi0358420;
RA Singh V., Shi W., Evans G.B., Tyler P.C., Furneaux R.H., Almo S.C.,
RA Schramm V.L.;
RT "Picomolar transition state analogue inhibitors of human 5'-
RT methylthioadenosine phosphorylase and X-ray structure with MT-
RT immucillin-A.";
RL Biochemistry 43:9-18(2004).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 227-237.
RX PubMed=20934997; DOI=10.3324/haematol.2010.030924;
RA Bade-Doding C., Theodossis A., Gras S., Kjer-Nielsen L.,
RA Eiz-Vesper B., Seltsam A., Huyton T., Rossjohn J., McCluskey J.,
RA Blasczyk R.;
RT "The impact of human leukocyte antigen (HLA) micropolymorphism on
RT ligand specificity within the HLA-B*41 allotypic family.";
RL Haematologica 96:110-118(2011).
CC -!- FUNCTION: Catalyzes the reversible phosphorylation of S-methyl-5'-
CC thioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate.
CC Involved in the breakdown of MTA, a major by-product of polyamine
CC biosynthesis. Responsible for the first step in the methionine
CC salvage pathway after MTA has been generated from S-
CC adenosylmethionine. Has broad substrate specificity with 6-
CC aminopurine nucleosides as preferred substrates.
CC -!- CATALYTIC ACTIVITY: S-methyl-5'-thioadenosine + phosphate =
CC adenine + S-methyl-5-thio-alpha-D-ribose 1-phosphate.
CC -!- ENZYME REGULATION: Inhibited by 5'-methylthiotubercin and 5'-
CC chloroformycin.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=5 uM for S-methyl-5'-thioadenosine;
CC KM=580 uM for phosphate;
CC KM=23 uM for adenine;
CC KM=8 uM for S-methyl-5-thio-alpha-D-ribose 1-phosphate;
CC pH dependence:
CC Optimum pH is 7.2-7.6;
CC -!- PATHWAY: Amino-acid biosynthesis; L-methionine biosynthesis via
CC salvage pathway; S-methyl-5-thio-alpha-D-ribose 1-phosphate from
CC S-methyl-5'-thioadenosine (phosphorylase route): step 1/1.
CC -!- SUBUNIT: Homotrimer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=7;
CC Name=1;
CC IsoId=Q13126-1; Sequence=Displayed;
CC Name=2; Synonyms=MTAP_v1;
CC IsoId=Q13126-2; Sequence=VSP_044074;
CC Name=3; Synonyms=MTAP_v2;
CC IsoId=Q13126-3; Sequence=VSP_044075;
CC Name=4; Synonyms=MTAP_v3;
CC IsoId=Q13126-4; Sequence=VSP_044076;
CC Name=5; Synonyms=MTAP_v4;
CC IsoId=Q13126-5; Sequence=VSP_044071;
CC Name=6; Synonyms=MTAP_v5;
CC IsoId=Q13126-6; Sequence=VSP_044072;
CC Name=7; Synonyms=MTAP_v6;
CC IsoId=Q13126-7; Sequence=VSP_044073;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed.
CC -!- DISEASE: Diaphyseal medullary stenosis with malignant fibrous
CC histiocytoma (DMSMFH) [MIM:112250]: An autosomal dominant bone
CC dysplasia characterized by pathologic fractures due to abnormal
CC cortical growth and diaphyseal medullary stenosis. The fractures
CC heal poorly, and there is progressive bowing of the lower
CC extremities. Some patients show a limb-girdle myopathy, with
CC muscle weakness and atrophy. Approximately 35% of affected
CC individuals develop an aggressive form of bone sarcoma consistent
CC with malignant fibrous histiocytoma or osteosarcoma. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry. DMSMFH causing mutations found in MTAP exon 9 result
CC in exon skipping and dysregulated alternative splicing of all MTAP
CC isoforms (PubMed:22464254).
CC -!- DISEASE: Note=Loss of MTAP activity may play a role in human
CC cancer. MTAP loss has been reported in a number of cancers,
CC including osteosarcoma, malignant melanoma and gastric cancer.
CC -!- SIMILARITY: Belongs to the PNP/MTAP phosphorylase family. MTAP
CC subfamily.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; U22233; AAA81646.1; -; mRNA.
DR EMBL; L40432; AAG38871.1; -; mRNA.
DR EMBL; L42634; AAR24607.2; -; Genomic_DNA.
DR EMBL; L42627; AAR24607.2; JOINED; Genomic_DNA.
DR EMBL; L42628; AAR24607.2; JOINED; Genomic_DNA.
DR EMBL; L42629; AAR24607.2; JOINED; Genomic_DNA.
DR EMBL; L42630; AAR24607.2; JOINED; Genomic_DNA.
DR EMBL; L42631; AAR24607.2; JOINED; Genomic_DNA.
DR EMBL; L42632; AAR24607.2; JOINED; Genomic_DNA.
DR EMBL; L42633; AAR24607.2; JOINED; Genomic_DNA.
DR EMBL; HE654772; CCF77345.1; -; mRNA.
DR EMBL; HE654773; CCF77346.1; -; mRNA.
DR EMBL; HE654774; CCF77347.1; -; mRNA.
DR EMBL; HE654775; CCF77348.1; -; mRNA.
DR EMBL; HE654776; CCF77349.1; -; mRNA.
DR EMBL; HE654777; CCF77350.1; -; mRNA.
DR EMBL; AY712791; AAU04442.1; -; mRNA.
DR EMBL; AL359922; CAI16481.1; -; Genomic_DNA.
DR EMBL; CH471071; EAW58606.1; -; Genomic_DNA.
DR EMBL; BC026106; AAH26106.1; -; mRNA.
DR PIR; I38969; I38969.
DR RefSeq; NP_002442.2; NM_002451.3.
DR RefSeq; XP_005251520.1; XM_005251463.1.
DR RefSeq; XP_005251521.1; XM_005251464.1.
DR UniGene; Hs.193268; -.
DR PDB; 1CB0; X-ray; 1.70 A; A=1-283.
DR PDB; 1CG6; X-ray; 1.70 A; A=1-283.
DR PDB; 1K27; X-ray; 1.95 A; A=1-283.
DR PDB; 1SD1; X-ray; 2.03 A; A=1-283.
DR PDB; 1SD2; X-ray; 2.10 A; A=1-283.
DR PDB; 3LN5; X-ray; 1.90 A; C=227-237.
DR PDB; 3OZC; X-ray; 1.93 A; A=1-283.
DR PDB; 3OZD; X-ray; 2.10 A; A/B=1-283.
DR PDB; 3OZE; X-ray; 2.00 A; A/B/C/D/E/F=1-283.
DR PDBsum; 1CB0; -.
DR PDBsum; 1CG6; -.
DR PDBsum; 1K27; -.
DR PDBsum; 1SD1; -.
DR PDBsum; 1SD2; -.
DR PDBsum; 3LN5; -.
DR PDBsum; 3OZC; -.
DR PDBsum; 3OZD; -.
DR PDBsum; 3OZE; -.
DR ProteinModelPortal; Q13126; -.
DR SMR; Q13126; 9-281.
DR IntAct; Q13126; 7.
DR MINT; MINT-268764; -.
DR STRING; 9606.ENSP00000369519; -.
DR BindingDB; Q13126; -.
DR ChEMBL; CHEMBL4941; -.
DR DrugBank; DB00173; Adenine.
DR PhosphoSite; Q13126; -.
DR DMDM; 143811423; -.
DR REPRODUCTION-2DPAGE; Q13126; -.
DR UCD-2DPAGE; Q13126; -.
DR PaxDb; Q13126; -.
DR PRIDE; Q13126; -.
DR DNASU; 4507; -.
DR Ensembl; ENST00000380172; ENSP00000369519; ENSG00000099810.
DR Ensembl; ENST00000580900; ENSP00000463424; ENSG00000099810.
DR GeneID; 4507; -.
DR KEGG; hsa:4507; -.
DR UCSC; uc003zph.3; human.
DR CTD; 4507; -.
DR GeneCards; GC09P021792; -.
DR H-InvDB; HIX0007954; -.
DR H-InvDB; HIX0025895; -.
DR HGNC; HGNC:7413; MTAP.
DR MIM; 112250; phenotype.
DR MIM; 156540; gene.
DR neXtProt; NX_Q13126; -.
DR Orphanet; 85182; Diaphyseal medullary stenosis - bone malignancy.
DR PharmGKB; PA31220; -.
DR eggNOG; COG0005; -.
DR HOGENOM; HOG000228986; -.
DR HOVERGEN; HBG002487; -.
DR InParanoid; Q13126; -.
DR KO; K00772; -.
DR OrthoDB; EOG771270; -.
DR PhylomeDB; Q13126; -.
DR BioCyc; MetaCyc:HS01913-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; Q13126; -.
DR SignaLink; Q13126; -.
DR UniPathway; UPA00904; UER00873.
DR ChiTaRS; MTAP; human.
DR EvolutionaryTrace; Q13126; -.
DR GeneWiki; MTAP; -.
DR GenomeRNAi; 4507; -.
DR NextBio; 17416; -.
DR PRO; PR:Q13126; -.
DR ArrayExpress; Q13126; -.
DR Bgee; Q13126; -.
DR CleanEx; HS_MTAP; -.
DR Genevestigator; Q13126; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0004645; F:phosphorylase activity; TAS:ProtInc.
DR GO; GO:0017061; F:S-methyl-5-thioadenosine phosphorylase activity; TAS:Reactome.
DR GO; GO:0019509; P:L-methionine salvage from methylthioadenosine; TAS:Reactome.
DR GO; GO:0006139; P:nucleobase-containing compound metabolic process; TAS:ProtInc.
DR GO; GO:0006595; P:polyamine metabolic process; TAS:Reactome.
DR GO; GO:0006166; P:purine ribonucleoside salvage; IEA:UniProtKB-KW.
DR Gene3D; 3.40.50.1580; -; 1.
DR HAMAP; MF_01963; MTAP; 1; -.
DR InterPro; IPR010044; MTAP.
DR InterPro; IPR000845; Nucleoside_phosphorylase_d.
DR InterPro; IPR001369; PNP/MTAP.
DR InterPro; IPR018099; Purine_phosphorylase-2_CS.
DR PANTHER; PTHR11904; PTHR11904; 1.
DR Pfam; PF01048; PNP_UDP_1; 1.
DR TIGRFAMs; TIGR01694; MTAP; 1.
DR PROSITE; PS01240; PNP_MTAP_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; Cytoplasm;
KW Glycosyltransferase; Nucleus; Polymorphism; Purine salvage;
KW Reference proteome; Transferase.
FT CHAIN 1 283 S-methyl-5'-thioadenosine phosphorylase.
FT /FTId=PRO_0000184545.
FT REGION 60 61 Phosphate binding.
FT REGION 93 94 Phosphate binding.
FT REGION 220 222 Substrate binding.
FT BINDING 18 18 Phosphate.
FT BINDING 196 196 Substrate; via amide nitrogen.
FT BINDING 197 197 Phosphate.
FT SITE 178 178 Important for substrate specificity.
FT SITE 233 233 Important for substrate specificity.
FT VAR_SEQ 231 283 VSVDRVLKTLKENANKAKSLLLTTIPQIGSTEWSETLHNLK
FT NMAQFSVLLPRH -> MIKFQMILSEGYHPFNIQESPFYRG
FT LLDFPSVGHGRGKKCLSAPAIILRPPQPRGTVTTFKVSWSK
FT DQTYICMKS (in isoform 5).
FT /FTId=VSP_044071.
FT VAR_SEQ 231 283 VSVDRVLKTLKENANKAKSLLLTTIPQIGSTEWSETLHNLK
FT NMAQFSVLLPRH -> MIKFQMILSEGYHPFNIQESPFYRG
FT LLDFPSVGHGRGEILPLSPLDLAGYCFQQPMQPPCPDS
FT (in isoform 6).
FT /FTId=VSP_044072.
FT VAR_SEQ 232 283 SVDRVLKTLKENANKAKSLLLTTIPQIGSTEWSETLHNLKN
FT MAQFSVLLPRH -> RSAFQLPP (in isoform 7).
FT /FTId=VSP_044073.
FT VAR_SEQ 272 283 NMAQFSVLLPRH -> MIKFQMILSEGYHPFNIQESPFYRG
FT LLDFPSVGHGRGKKCLSAPAIILRPPQPRGTVTTFKVSWSK
FT DQTYICMKS (in isoform 2).
FT /FTId=VSP_044074.
FT VAR_SEQ 272 283 NMAQFSVLLPRH -> MIKFQMILSEGYHPFNIQESPFYRG
FT LLDFPSVGHGRGEILPLSPLDLAGYCFQQPMQPPCPDS
FT (in isoform 3).
FT /FTId=VSP_044075.
FT VAR_SEQ 272 283 NMAQFSVLLPRH -> VRSAFQLPP (in isoform 4).
FT /FTId=VSP_044076.
FT VARIANT 56 56 V -> I (in dbSNP:rs7023954).
FT /FTId=VAR_031470.
FT CONFLICT 218 218 A -> G (in Ref. 2; AAG38871/AAR24607).
FT STRAND 11 16
FT HELIX 23 25
FT STRAND 26 32
FT STRAND 45 50
FT STRAND 53 59
FT TURN 60 65
FT HELIX 69 71
FT HELIX 74 83
FT STRAND 87 97
FT STRAND 107 109
FT STRAND 112 116
FT STRAND 126 128
FT STRAND 134 136
FT STRAND 140 142
FT HELIX 146 158
FT STRAND 163 165
FT STRAND 168 172
FT HELIX 180 188
FT STRAND 193 197
FT HELIX 198 207
FT STRAND 211 220
FT TURN 222 224
FT STRAND 225 228
FT HELIX 233 258
FT HELIX 264 275
SQ SEQUENCE 283 AA; 31236 MW; 3B34C565EB5B99DA CRC64;
MASGTTTTAV KIGIIGGTGL DDPEILEGRT EKYVDTPFGK PSDALILGKI KNVDCVLLAR
HGRQHTIMPS KVNYQANIWA LKEEGCTHVI VTTACGSLRE EIQPGDIVII DQFIDRTTMR
PQSFYDGSHS CARGVCHIPM AEPFCPKTRE VLIETAKKLG LRCHSKGTMV TIEGPRFSSR
AESFMFRTWG ADVINMTTVP EVVLAKEAGI CYASIAMATD YDCWKEHEEA VSVDRVLKTL
KENANKAKSL LLTTIPQIGS TEWSETLHNL KNMAQFSVLL PRH
//
ID MTAP_HUMAN Reviewed; 283 AA.
AC Q13126; I2G7M5; I2G7M6; I2G7M7; I2G7M8; I2G7M9; I2G7N0; Q5T3P3;
read moreAC Q9H010;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 03-APR-2007, sequence version 2.
DT 22-JAN-2014, entry version 145.
DE RecName: Full=S-methyl-5'-thioadenosine phosphorylase;
DE EC=2.4.2.28;
DE AltName: Full=5'-methylthioadenosine phosphorylase;
DE Short=MTA phosphorylase;
DE Short=MTAP;
DE Short=MTAPase;
GN Name=MTAP; Synonyms=MSAP;
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], AND VARIANT ILE-56.
RC TISSUE=Epidermis;
RX PubMed=7604019; DOI=10.1073/pnas.92.14.6489;
RA Olopade O.I., Pomykala H.M., Hagos F., Sveen L.W., Espinosa R. III,
RA Dreyling M.H., Gursky S., Stadler W.M., le Beau M.M., Bohlander S.K.;
RT "Construction of a 2.8-megabase yeast artificial chromosome contig and
RT cloning of the human methylthioadenosine phosphorylase gene from the
RT tumor suppressor region on 9p21.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:6489-6493(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RC TISSUE=Placenta;
RX PubMed=8650244; DOI=10.1073/pnas.93.12.6203;
RA Nobori T., Takabayashi K., Tran P., Orvis L., Batova A., Yu A.L.,
RA Carson D.A.;
RT "Genomic cloning of methylthioadenosine phosphorylase: a purine
RT metabolic enzyme deficient in multiple different cancers.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:6203-6208(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 3; 4; 5; 6 AND 7), AND
RP INVOLVEMENT IN DMSMFH.
RX PubMed=22464254; DOI=10.1016/j.ajhg.2012.02.024;
RA Camacho-Vanegas O., Camacho S.C., Till J., Miranda-Lorenzo I.,
RA Terzo E., Ramirez M.C., Schramm V., Cordovano G., Watts G., Mehta S.,
RA Kimonis V., Hoch B., Philibert K.D., Raabe C.A., Bishop D.F.,
RA Glucksman M.J., Martignetti J.A.;
RT "Primate genome gain and loss: a bone dysplasia, muscular dystrophy,
RT and bone cancer syndrome resulting from mutated retroviral-derived
RT MTAP transcripts.";
RL Am. J. Hum. Genet. 90:614-627(2012).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ILE-56.
RC TISSUE=Colon;
RA Li Q., Cao W.-X., Zhang Y., Shi M.-M., Liu B.-Y., Zhu Z.-G.,
RA Lin Y.-Z.;
RT "Identification of human methylthioadenosine phosphorylase (MTAP) mRNA
RT mutation in colon cancer cell line COLO 205.";
RL Submitted (AUG-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [6]
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ILE-56.
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, AND SUBUNIT.
RX PubMed=3091600;
RA Della Ragione F., Carteni-Farina M., Gragnaniello V., Schettino M.I.,
RA Zappia V.;
RT "Purification and characterization of 5'-deoxy-5'-methylthioadenosine
RT phosphorylase from human placenta.";
RL J. Biol. Chem. 261:12324-12329(1986).
RN [9]
RP BIOPHYSICOCHEMICAL PROPERTIES, AND SUBUNIT.
RX PubMed=8687427; DOI=10.1006/bbrc.1996.0926;
RA Ragione F.D., Takabayashi K., Mastropietro S., Mercurio C., Oliva A.,
RA Russo G.L., Pietra V.D., Borriello A., Nobori T., Carson D.A.,
RA Zappia V.;
RT "Purification and characterization of recombinant human 5'-
RT methylthioadenosine phosphorylase: definite identification of coding
RT cDNA.";
RL Biochem. Biophys. Res. Commun. 223:514-519(1996).
RN [10]
RP INVOLVEMENT IN OSTEOSARCOMA.
RX PubMed=11895909;
RA Garcia-Castellano J.M., Villanueva A., Healey J.H., Sowers R.,
RA Cordon-Cardo C., Huvos A., Bertino J.R., Meyers P., Gorlick R.;
RT "Methylthioadenosine phosphorylase gene deletions are common in
RT osteosarcoma.";
RL Clin. Cancer Res. 8:782-787(2002).
RN [11]
RP INVOLVEMENT IN OSTEOSARCOMA.
RX PubMed=17912432;
RA Miyazaki S., Nishioka J., Shiraishi T., Matsumine A., Uchida A.,
RA Nobori T.;
RT "Methylthioadenosine phosphorylase deficiency in Japanese osteosarcoma
RT patients.";
RL Int. J. Oncol. 31:1069-1076(2007).
RN [12]
RP INVOLVEMENT IN MALIGNANT MELANOMA.
RX PubMed=19097084; DOI=10.1002/jcb.21984;
RA Stevens A.P., Spangler B., Wallner S., Kreutz M., Dettmer K.,
RA Oefner P.J., Bosserhoff A.K.;
RT "Direct and tumor microenvironment mediated influences of 5'-deoxy-5'-
RT (methylthio)adenosine on tumor progression of malignant melanoma.";
RL J. Cell. Biochem. 106:210-219(2009).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [14]
RP INVOLVEMENT IN GASTRIC CANCER.
RX PubMed=21412930; DOI=10.1002/gcc.20867;
RA Kim J., Kim M.A., Min S.Y., Jee C.D., Lee H.E., Kim W.H.;
RT "Downregulation of methylthioadenosine phosphorylase by homozygous
RT deletion in gastric carcinoma.";
RL Genes Chromosomes Cancer 50:421-433(2011).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) IN COMPLEX WITH MTA.
RX PubMed=10404592; DOI=10.1016/S0969-2126(99)80084-7;
RA Appleby T.C., Erion M.D., Ealick S.E.;
RT "The structure of human 5'-deoxy-5'-methylthioadenosine phosphorylase
RT at 1.7-A resolution provides insights into substrate binding and
RT catalysis.";
RL Structure 7:629-641(1999).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.03 ANGSTROMS) IN COMPLEX WITH SUBSTRATE
RP ANALOGS.
RX PubMed=15122881; DOI=10.1021/bi035492h;
RA Lee J.E., Settembre E.C., Cornell K.A., Riscoe M.K., Sufrin J.R.,
RA Ealick S.E., Howell P.L.;
RT "Structural comparison of MTA phosphorylase and MTA/AdoHcy
RT nucleosidase explains substrate preferences and identifies regions
RT exploitable for inhibitor design.";
RL Biochemistry 43:5159-5169(2004).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) IN COMPLEX WITH INHIBITORS.
RX PubMed=14705926; DOI=10.1021/bi0358420;
RA Singh V., Shi W., Evans G.B., Tyler P.C., Furneaux R.H., Almo S.C.,
RA Schramm V.L.;
RT "Picomolar transition state analogue inhibitors of human 5'-
RT methylthioadenosine phosphorylase and X-ray structure with MT-
RT immucillin-A.";
RL Biochemistry 43:9-18(2004).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 227-237.
RX PubMed=20934997; DOI=10.3324/haematol.2010.030924;
RA Bade-Doding C., Theodossis A., Gras S., Kjer-Nielsen L.,
RA Eiz-Vesper B., Seltsam A., Huyton T., Rossjohn J., McCluskey J.,
RA Blasczyk R.;
RT "The impact of human leukocyte antigen (HLA) micropolymorphism on
RT ligand specificity within the HLA-B*41 allotypic family.";
RL Haematologica 96:110-118(2011).
CC -!- FUNCTION: Catalyzes the reversible phosphorylation of S-methyl-5'-
CC thioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate.
CC Involved in the breakdown of MTA, a major by-product of polyamine
CC biosynthesis. Responsible for the first step in the methionine
CC salvage pathway after MTA has been generated from S-
CC adenosylmethionine. Has broad substrate specificity with 6-
CC aminopurine nucleosides as preferred substrates.
CC -!- CATALYTIC ACTIVITY: S-methyl-5'-thioadenosine + phosphate =
CC adenine + S-methyl-5-thio-alpha-D-ribose 1-phosphate.
CC -!- ENZYME REGULATION: Inhibited by 5'-methylthiotubercin and 5'-
CC chloroformycin.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=5 uM for S-methyl-5'-thioadenosine;
CC KM=580 uM for phosphate;
CC KM=23 uM for adenine;
CC KM=8 uM for S-methyl-5-thio-alpha-D-ribose 1-phosphate;
CC pH dependence:
CC Optimum pH is 7.2-7.6;
CC -!- PATHWAY: Amino-acid biosynthesis; L-methionine biosynthesis via
CC salvage pathway; S-methyl-5-thio-alpha-D-ribose 1-phosphate from
CC S-methyl-5'-thioadenosine (phosphorylase route): step 1/1.
CC -!- SUBUNIT: Homotrimer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=7;
CC Name=1;
CC IsoId=Q13126-1; Sequence=Displayed;
CC Name=2; Synonyms=MTAP_v1;
CC IsoId=Q13126-2; Sequence=VSP_044074;
CC Name=3; Synonyms=MTAP_v2;
CC IsoId=Q13126-3; Sequence=VSP_044075;
CC Name=4; Synonyms=MTAP_v3;
CC IsoId=Q13126-4; Sequence=VSP_044076;
CC Name=5; Synonyms=MTAP_v4;
CC IsoId=Q13126-5; Sequence=VSP_044071;
CC Name=6; Synonyms=MTAP_v5;
CC IsoId=Q13126-6; Sequence=VSP_044072;
CC Name=7; Synonyms=MTAP_v6;
CC IsoId=Q13126-7; Sequence=VSP_044073;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed.
CC -!- DISEASE: Diaphyseal medullary stenosis with malignant fibrous
CC histiocytoma (DMSMFH) [MIM:112250]: An autosomal dominant bone
CC dysplasia characterized by pathologic fractures due to abnormal
CC cortical growth and diaphyseal medullary stenosis. The fractures
CC heal poorly, and there is progressive bowing of the lower
CC extremities. Some patients show a limb-girdle myopathy, with
CC muscle weakness and atrophy. Approximately 35% of affected
CC individuals develop an aggressive form of bone sarcoma consistent
CC with malignant fibrous histiocytoma or osteosarcoma. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry. DMSMFH causing mutations found in MTAP exon 9 result
CC in exon skipping and dysregulated alternative splicing of all MTAP
CC isoforms (PubMed:22464254).
CC -!- DISEASE: Note=Loss of MTAP activity may play a role in human
CC cancer. MTAP loss has been reported in a number of cancers,
CC including osteosarcoma, malignant melanoma and gastric cancer.
CC -!- SIMILARITY: Belongs to the PNP/MTAP phosphorylase family. MTAP
CC subfamily.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; U22233; AAA81646.1; -; mRNA.
DR EMBL; L40432; AAG38871.1; -; mRNA.
DR EMBL; L42634; AAR24607.2; -; Genomic_DNA.
DR EMBL; L42627; AAR24607.2; JOINED; Genomic_DNA.
DR EMBL; L42628; AAR24607.2; JOINED; Genomic_DNA.
DR EMBL; L42629; AAR24607.2; JOINED; Genomic_DNA.
DR EMBL; L42630; AAR24607.2; JOINED; Genomic_DNA.
DR EMBL; L42631; AAR24607.2; JOINED; Genomic_DNA.
DR EMBL; L42632; AAR24607.2; JOINED; Genomic_DNA.
DR EMBL; L42633; AAR24607.2; JOINED; Genomic_DNA.
DR EMBL; HE654772; CCF77345.1; -; mRNA.
DR EMBL; HE654773; CCF77346.1; -; mRNA.
DR EMBL; HE654774; CCF77347.1; -; mRNA.
DR EMBL; HE654775; CCF77348.1; -; mRNA.
DR EMBL; HE654776; CCF77349.1; -; mRNA.
DR EMBL; HE654777; CCF77350.1; -; mRNA.
DR EMBL; AY712791; AAU04442.1; -; mRNA.
DR EMBL; AL359922; CAI16481.1; -; Genomic_DNA.
DR EMBL; CH471071; EAW58606.1; -; Genomic_DNA.
DR EMBL; BC026106; AAH26106.1; -; mRNA.
DR PIR; I38969; I38969.
DR RefSeq; NP_002442.2; NM_002451.3.
DR RefSeq; XP_005251520.1; XM_005251463.1.
DR RefSeq; XP_005251521.1; XM_005251464.1.
DR UniGene; Hs.193268; -.
DR PDB; 1CB0; X-ray; 1.70 A; A=1-283.
DR PDB; 1CG6; X-ray; 1.70 A; A=1-283.
DR PDB; 1K27; X-ray; 1.95 A; A=1-283.
DR PDB; 1SD1; X-ray; 2.03 A; A=1-283.
DR PDB; 1SD2; X-ray; 2.10 A; A=1-283.
DR PDB; 3LN5; X-ray; 1.90 A; C=227-237.
DR PDB; 3OZC; X-ray; 1.93 A; A=1-283.
DR PDB; 3OZD; X-ray; 2.10 A; A/B=1-283.
DR PDB; 3OZE; X-ray; 2.00 A; A/B/C/D/E/F=1-283.
DR PDBsum; 1CB0; -.
DR PDBsum; 1CG6; -.
DR PDBsum; 1K27; -.
DR PDBsum; 1SD1; -.
DR PDBsum; 1SD2; -.
DR PDBsum; 3LN5; -.
DR PDBsum; 3OZC; -.
DR PDBsum; 3OZD; -.
DR PDBsum; 3OZE; -.
DR ProteinModelPortal; Q13126; -.
DR SMR; Q13126; 9-281.
DR IntAct; Q13126; 7.
DR MINT; MINT-268764; -.
DR STRING; 9606.ENSP00000369519; -.
DR BindingDB; Q13126; -.
DR ChEMBL; CHEMBL4941; -.
DR DrugBank; DB00173; Adenine.
DR PhosphoSite; Q13126; -.
DR DMDM; 143811423; -.
DR REPRODUCTION-2DPAGE; Q13126; -.
DR UCD-2DPAGE; Q13126; -.
DR PaxDb; Q13126; -.
DR PRIDE; Q13126; -.
DR DNASU; 4507; -.
DR Ensembl; ENST00000380172; ENSP00000369519; ENSG00000099810.
DR Ensembl; ENST00000580900; ENSP00000463424; ENSG00000099810.
DR GeneID; 4507; -.
DR KEGG; hsa:4507; -.
DR UCSC; uc003zph.3; human.
DR CTD; 4507; -.
DR GeneCards; GC09P021792; -.
DR H-InvDB; HIX0007954; -.
DR H-InvDB; HIX0025895; -.
DR HGNC; HGNC:7413; MTAP.
DR MIM; 112250; phenotype.
DR MIM; 156540; gene.
DR neXtProt; NX_Q13126; -.
DR Orphanet; 85182; Diaphyseal medullary stenosis - bone malignancy.
DR PharmGKB; PA31220; -.
DR eggNOG; COG0005; -.
DR HOGENOM; HOG000228986; -.
DR HOVERGEN; HBG002487; -.
DR InParanoid; Q13126; -.
DR KO; K00772; -.
DR OrthoDB; EOG771270; -.
DR PhylomeDB; Q13126; -.
DR BioCyc; MetaCyc:HS01913-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; Q13126; -.
DR SignaLink; Q13126; -.
DR UniPathway; UPA00904; UER00873.
DR ChiTaRS; MTAP; human.
DR EvolutionaryTrace; Q13126; -.
DR GeneWiki; MTAP; -.
DR GenomeRNAi; 4507; -.
DR NextBio; 17416; -.
DR PRO; PR:Q13126; -.
DR ArrayExpress; Q13126; -.
DR Bgee; Q13126; -.
DR CleanEx; HS_MTAP; -.
DR Genevestigator; Q13126; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0004645; F:phosphorylase activity; TAS:ProtInc.
DR GO; GO:0017061; F:S-methyl-5-thioadenosine phosphorylase activity; TAS:Reactome.
DR GO; GO:0019509; P:L-methionine salvage from methylthioadenosine; TAS:Reactome.
DR GO; GO:0006139; P:nucleobase-containing compound metabolic process; TAS:ProtInc.
DR GO; GO:0006595; P:polyamine metabolic process; TAS:Reactome.
DR GO; GO:0006166; P:purine ribonucleoside salvage; IEA:UniProtKB-KW.
DR Gene3D; 3.40.50.1580; -; 1.
DR HAMAP; MF_01963; MTAP; 1; -.
DR InterPro; IPR010044; MTAP.
DR InterPro; IPR000845; Nucleoside_phosphorylase_d.
DR InterPro; IPR001369; PNP/MTAP.
DR InterPro; IPR018099; Purine_phosphorylase-2_CS.
DR PANTHER; PTHR11904; PTHR11904; 1.
DR Pfam; PF01048; PNP_UDP_1; 1.
DR TIGRFAMs; TIGR01694; MTAP; 1.
DR PROSITE; PS01240; PNP_MTAP_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; Cytoplasm;
KW Glycosyltransferase; Nucleus; Polymorphism; Purine salvage;
KW Reference proteome; Transferase.
FT CHAIN 1 283 S-methyl-5'-thioadenosine phosphorylase.
FT /FTId=PRO_0000184545.
FT REGION 60 61 Phosphate binding.
FT REGION 93 94 Phosphate binding.
FT REGION 220 222 Substrate binding.
FT BINDING 18 18 Phosphate.
FT BINDING 196 196 Substrate; via amide nitrogen.
FT BINDING 197 197 Phosphate.
FT SITE 178 178 Important for substrate specificity.
FT SITE 233 233 Important for substrate specificity.
FT VAR_SEQ 231 283 VSVDRVLKTLKENANKAKSLLLTTIPQIGSTEWSETLHNLK
FT NMAQFSVLLPRH -> MIKFQMILSEGYHPFNIQESPFYRG
FT LLDFPSVGHGRGKKCLSAPAIILRPPQPRGTVTTFKVSWSK
FT DQTYICMKS (in isoform 5).
FT /FTId=VSP_044071.
FT VAR_SEQ 231 283 VSVDRVLKTLKENANKAKSLLLTTIPQIGSTEWSETLHNLK
FT NMAQFSVLLPRH -> MIKFQMILSEGYHPFNIQESPFYRG
FT LLDFPSVGHGRGEILPLSPLDLAGYCFQQPMQPPCPDS
FT (in isoform 6).
FT /FTId=VSP_044072.
FT VAR_SEQ 232 283 SVDRVLKTLKENANKAKSLLLTTIPQIGSTEWSETLHNLKN
FT MAQFSVLLPRH -> RSAFQLPP (in isoform 7).
FT /FTId=VSP_044073.
FT VAR_SEQ 272 283 NMAQFSVLLPRH -> MIKFQMILSEGYHPFNIQESPFYRG
FT LLDFPSVGHGRGKKCLSAPAIILRPPQPRGTVTTFKVSWSK
FT DQTYICMKS (in isoform 2).
FT /FTId=VSP_044074.
FT VAR_SEQ 272 283 NMAQFSVLLPRH -> MIKFQMILSEGYHPFNIQESPFYRG
FT LLDFPSVGHGRGEILPLSPLDLAGYCFQQPMQPPCPDS
FT (in isoform 3).
FT /FTId=VSP_044075.
FT VAR_SEQ 272 283 NMAQFSVLLPRH -> VRSAFQLPP (in isoform 4).
FT /FTId=VSP_044076.
FT VARIANT 56 56 V -> I (in dbSNP:rs7023954).
FT /FTId=VAR_031470.
FT CONFLICT 218 218 A -> G (in Ref. 2; AAG38871/AAR24607).
FT STRAND 11 16
FT HELIX 23 25
FT STRAND 26 32
FT STRAND 45 50
FT STRAND 53 59
FT TURN 60 65
FT HELIX 69 71
FT HELIX 74 83
FT STRAND 87 97
FT STRAND 107 109
FT STRAND 112 116
FT STRAND 126 128
FT STRAND 134 136
FT STRAND 140 142
FT HELIX 146 158
FT STRAND 163 165
FT STRAND 168 172
FT HELIX 180 188
FT STRAND 193 197
FT HELIX 198 207
FT STRAND 211 220
FT TURN 222 224
FT STRAND 225 228
FT HELIX 233 258
FT HELIX 264 275
SQ SEQUENCE 283 AA; 31236 MW; 3B34C565EB5B99DA CRC64;
MASGTTTTAV KIGIIGGTGL DDPEILEGRT EKYVDTPFGK PSDALILGKI KNVDCVLLAR
HGRQHTIMPS KVNYQANIWA LKEEGCTHVI VTTACGSLRE EIQPGDIVII DQFIDRTTMR
PQSFYDGSHS CARGVCHIPM AEPFCPKTRE VLIETAKKLG LRCHSKGTMV TIEGPRFSSR
AESFMFRTWG ADVINMTTVP EVVLAKEAGI CYASIAMATD YDCWKEHEEA VSVDRVLKTL
KENANKAKSL LLTTIPQIGS TEWSETLHNL KNMAQFSVLL PRH
//
MIM
112250
*RECORD*
*FIELD* NO
112250
*FIELD* TI
#112250 DIAPHYSEAL MEDULLARY STENOSIS WITH MALIGNANT FIBROUS HISTIOCYTOMA;
DMSMFH
;;BONE DYSPLASIA WITH MEDULLARY FIBROSARCOMA; BDMF;;
read moreBONE DYSPLASIA WITH MALIGNANT FIBROUS HISTIOCYTOMA;;
MYOPATHY, LIMB-GIRDLE, WITH BONE FRAGILITY
*FIELD* TX
A number sign (#) is used with this entry because diaphyseal medullary
stenosis with malignant fibrous histiocytoma (DMSMFH) is caused by
heterozygous mutation in the MTAP gene (156540) on chromosome 9p21.
DESCRIPTION
Diaphyseal medullary stenosis with malignant fibrous histiocytoma is an
autosomal dominant bone dysplasia characterized by pathologic fractures
due to abnormal cortical growth and diaphyseal medullary stenosis. The
fractures heal poorly, and there is progressive bowing of the lower
extremities. In 2 families, affected individuals also showed a
limb-girdle myopathy, with muscle weakness and atrophy. Approximately
35% of affected individuals develop an aggressive form of bone sarcoma
consistent with malignant fibrous histiocytoma or osteosarcoma. Thus,
the disorder may be considered a tumor predisposition syndrome (summary
by Camacho-Vanegas et al., 2012).
CLINICAL FEATURES
Arnold (1973) described several generations of a Vermont and New York
kindred demonstrating multiple areas of necrosis in the diaphyses of the
large tubular bones. The radiographic appearance of this skeletal
condition resembled radiation osteitis, a highly premalignant condition;
however, no source of radiation exposure was found in this family.
Medullary fibrosarcoma, an uncommon bone tumor, was noted in 4 of the 12
affected members. Death had occurred from widespread metastases at ages
varying from 23 to 48 years. Occurrence of fibrosarcoma in idiopathic
bone infarcts (Furey et al., 1960) and in an infarct in a caisson worker
(Dorfman et al., 1966) has been reported. Camacho-Vanegas et al. (2012)
noted that 2 affected male individuals in the family reported by Arnold
(1973) died of heart disease in their early forties without other known
risk factors, and suggested that this may be a manifestation of the
disorder.
Hardcastle et al. (1986) gave follow-up information on the original
American family and reported 2 other families, one English and the other
Australian. They could find no reports of any hereditary or acquired
condition similar to that in these 3 families. They suggested that the
malignant change should be labeled 'malignant fibrous histiocytoma'
rather than fibrosarcoma because the tumors were markedly aggressive.
The malignancy occurred generally in the second to fifth decades of
life. They defined the skeletal dysplasia as a diaphyseal medullary
stenosis with overlying cortical bone thickening. The occurrence of
fracture with minimal trauma was emphasized.
Norton et al. (1996) reported a 19-year-old boy who presented with a
nontender mass on the left tibia that proved to be a pleiomorphic
spindle cell sarcoma. Radiographs of the affected leg showed extensive
diaphyseal cortical thickening and a medullary permeative pattern in the
diaphysis. Radiographs of the patient's mother and maternal grandmother
showed a similar bony dysplasia, with areas of infarction and medullary
sclerosis. The lower extremities were more affected than the upper
extremities in all 3 cases. Family history was significant for the death
of the maternal great-grandmother at age 32 from 'metastatic
osteosarcoma.' Norton et al. (1996) commented on the similarities to the
families reported by Hardcastle et al. (1986) and noted that the
malignant fibrous histiocytomas in this condition presumably begin at
the sites of infarction within the affected bone.
Henry et al. (1958) reported a Canadian family in which 6 men had
delayed healing of fractures of the long bones and later developed
myopathy. Mehta et al. (2006) provided follow-up on the family reported
by Henry et al. (1958); features of 8 living and 8 deceased family
members with the disorder were evaluated. In this family, fractures
preceded myopathy: the average age at onset of limb-girdle myopathy was
31 years, whereas that of fractures was 24 years. Fractures were
primarily of the long bones of the lower limbs and were associated with
poor healing and osteomyelitis, leading to amputation in some cases.
Serum creatine kinase was mildly increased, and alkaline phosphatase was
normal. Radiographs showed coarse trabeculation, patchy sclerosis,
cortical thickening, and narrowing of the medullary cavities of the long
bones. The findings were not consistent with Paget disease (602080).
Muscle biopsies showed nonspecific myopathic changes without necrotic
fibers, regenerating fibers, inflammatory infiltrates, or structural
abnormalities. Many affected family members had premature graying of the
hair and soft, thin skin, and 3 affected members had a clotting
disorder.
INHERITANCE
The transmission patterns in the families with DMSMFH reported by Arnold
(1973), Hardcastle et al. (1986), Norton et al. (1996), and Mehta et al.
(2006) were all consistent with autosomal dominant inheritance.
MAPPING
Martignetti et al. (1997, 1999) used microsatellite markers in a genome
screen for the gene locus in diaphyseal medullary stenosis with
malignant fibrous histiocytoma in 3 unrelated families. They linked the
syndrome to a region of approximately 3 cM on 9p22-p21, with a maximum
2-point lod score of 5.49 with marker D9S171 at recombination fraction
(theta) 0.05. This region of chromosome 9 is the site of chromosomal
abnormalities in several other malignancies and contains a number of
genes whose protein products are involved in growth regulation.
Identification of the gene responsible for this rare familial sarcoma
would be expected to define as well the cause of the more common
nonfamilial, or sporadic, form of malignant fibrous histiocytoma, a
tumor that constitutes approximately 6% of all bone cancers and is the
most frequently occurring adult soft-tissue sarcoma.
To determine whether the hereditary and sporadic forms of bone dysplasia
with malignant fibrous histiocytoma are genetically linked, Martignetti
et al. (2000) performed loss of heterozygosity (LOH) studies of the
9p22-9p21 region and found that 71% (5/7) of informative sporadic DMSMFH
specimens displayed LOH for markers within that same region. Definition
of the minimal region of LOH overlap effectively limited the DMSMFH gene
to a 2-cM region between markers D9S736 and D9S171.
By genomewide linkage analysis of the family reported by Henry et al.
(1958) and Mehta et al. (2006), Watts et al. (2005) identified a
candidate disease locus on chromosome 9p22-p21 (maximum lod score of
3.74 at marker D9S1121). Haplotype analysis refined the locus to a 15-Mb
region. Genetic analysis excluded mutations in the ADAMTSL1 (609198) and
TYRP1 (115501) genes. Watts et al. (2005) noted that the clinical
phenotype in this family and the identified locus overlap with
diaphyseal medullary stenosis with malignant fibrous histiocytoma.
MOLECULAR GENETICS
Camacho-Vanegas et al. (2012) identified 2 different heterozygous
mutations affecting exon 9 of the MTAP gene (156540.0001 and
156540.0002) in affected members of 5 unrelated families with diaphyseal
medullary stenosis with malignant fibrous histiocytoma. Four of the
families had previously been reported by Arnold (1973), Hardcastle et
al. (1986), Norton et al. (1996), and Watts et al. (2005). The mutations
were found by positional cloning and examination of putative open
reading frames within the candidate region. The analysis identified
previously unrecognized exons in the MTAP gene, including exon 9. Both
mutations affected splicing, with altered expression of MTAP isoforms.
Serum samples from 2 patients showed accumulation of methylthioadenosine
(MTA), whereas MTA was not present in serum from 3 controls. These
findings implicated a defect in MTAP enzyme activity in the patients
with mutations. DNA analysis of tumor tissue from an osteosarcoma of 1
patient showed homozygosity for the mutation with loss of heterozygosity
of the wildtype allele. The findings of the study suggested that MTAP
can also act as a tumor suppressor gene.
*FIELD* RF
1. Arnold, W. H.: Hereditary bone dysplasia with sarcomatous degeneration. Ann.
Intern. Med. 78: 902-906, 1973.
2. Camacho-Vanegas, O.; Camacho, S. C.; Till, J.; Miranda-Lorenzo,
I.; Terzo, E.; Ramirez, M. C.; Schramm, V.; Cordovano, G.; Watts,
G.; Mehta, S.; Kimonis, V.; Hoch, B.; Philibert, K. D.; Raabe, C.
A.; Bishop, D. F.; Glucksman, M. J.; Martignetti, J. A.: Primate
genome gain and loss: a bone dysplasia, muscular dystrophy, and bone
cancer syndrome resulting from mutated retroviral-derived MTAP transcripts. Am.
J. Hum. Genet. 90: 614-627, 2012.
3. Dorfman, H. D.; Norman, A.; Wolff, H.: Fibrosarcoma complicating
bone infarction in a caisson worker. J. Bone Joint Surg. Am. 48:
528-532, 1966.
4. Furey, J. G.; Ferrer-Torells, M.; Reagan, J. W.: Fibrosarcoma
arising at the site of bone infarcts. J. Bone Joint Surg. Am. 42:
802-810, 1960.
5. Hardcastle, P.; Nade, S.; Arnold, W.: Hereditary bone dysplasia
with malignant change: report of three families. J. Bone Joint Surg.
Am. 68: 1079-1089, 1986.
6. Henry, E. W.; Auckland, N. L.; McIntosh, H. W.; Starr, D. E.:
Abnormality of the long bones and progressive muscular dystrophy in
a family. Canad. Med. Assoc. J. 78: 331-336, 1958.
7. Martignetti, J. A.; Desnick, R. J.; Aliprandis, E.; Norton, K.
I.; Hardcastle, P.; Nade, S.; Gelb, B. D.: Diaphyseal medullary stenosis
with malignant fibrous histiocytoma: a hereditary bone dysplasia/cancer
syndrome maps to 9p21-22. Am. J. Hum. Genet. 64: 801-807, 1999.
8. Martignetti, J. A.; Desnick, R. J.; Norton, K.; Hardcastle, P.;
Nade, S.; Gelb, B. D.: Genetic linkage of hereditary bone dysplasia
with malignant changes to chromosome 9p21-22. (Abstract) Am. J. Hum.
Genet. 61 (suppl.): A284 only, 1997.
9. Martignetti, J. A.; Gelb, B. D.; Pierce, H.; Picci, P.; Desnick,
R. J.: Malignant fibrous histiocytoma: inherited and sporadic forms
have loss of heterozygosity at chromosome bands 9p21-p22--evidence
for a common genetic defect. Genes Chromosomes Cancer 27: 191-195,
2000.
10. Mehta, S. G.; Watts, G. D. J.; McGillivray, B.; Mumm, S.; Hamilton,
S. J.; Ramdeen, S.; Novack, D.; Briggs, C.; Whyte, M. P.; Kimonis,
V. E.: Manifestations in a family with autosomal dominant bone fragility
and limb-girdle myopathy. Am. J. Med. Genet. 140A: 322-330, 2006.
11. Norton, K. I.; Wagreich, J. M.; Granowetter, L.; Martignetti,
J. A.: Diaphyseal medullary stenosis (sclerosis) with bone malignancy
(malignant fibrous histiocytoma): Hardcastle syndrome. Pediat. Radiol. 26:
675-677, 1996.
12. Watts, G. D. J.; Mehta, S. G.; Zhao, C.; Ramdeen, S.; Hamilton,
S. J.; Novack, D. V.; Mumm, S.; Whyte, M. P.; McGillivray, B.; Kimonis,
V. E.: Mapping autosomal dominant progressive limb-girdle myopathy
with bone fragility to chromosome 9p21-p22: a novel locus for a musculoskeletal
syndrome. Hum. Genet. 118: 508-514, 2005.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Presenile cataracts
SKELETAL:
Osteopenia;
Radiolucency of the bones;
[Limbs];
Bony dysplasia;
Pathologic fractures of the long bones;
Osteomyelitis leading to amputation due to slow healing fractures;
Patchy sclerotic changes to the long bones;
Coarse, sclerotic trabeculae;
Diaphyseal cortical thickening;
Diaphyseal medullary stenosis;
Metaphyseal striations;
Necrosis in large tubular bone diaphyses;
Narrow medullary cavities;
Marrow necrosis;
Marrow infarctions;
Bowing of the lower extremities
SKIN, NAILS, HAIR:
[Skin];
Soft, thin skin (1 family);
Easy bruising (1 family);
[Hair];
Premature graying (1 family)
MUSCLE, SOFT TISSUE:
Limb-girdle muscle weakness (2 families);
Proximal muscle weakness;
Proximal and distal muscle atrophy;
Distal limb muscle weakness occurs later;
Myopathic changes seen on EMG and muscle biopsy
NEOPLASIA:
Malignant fibrous histiocytoma (in about 35% of patients);
Osteosarcoma;
Fibrosarcoma
LABORATORY ABNORMALITIES:
Serum alkaline phosphatase normal or mildly increased;
Serum creatine kinase normal or mildly increased
MISCELLANEOUS:
Mean age at onset of bone fractures, 24 years;
Mean age at onset of proximal muscle weakness, 31 years;
Progressive disorder;
Not all patients have a myopathy;
Most become wheelchair-bound late in life
MOLECULAR BASIS:
Caused by mutation in the methylthioadenosine phosphorylase gene (MTAP,
156540.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 5/3/2012
*FIELD* CD
John F. Jackson: 6/15/1996
*FIELD* ED
joanna: 05/16/2012
joanna: 5/4/2012
ckniffin: 5/3/2012
joanna: 10/26/2006
ckniffin: 2/28/2006
*FIELD* CN
Cassandra L. Kniffin - updated: 5/3/2012
Victor A. McKusick - updated: 3/2/2000
Victor A. McKusick - updated: 3/22/1999
Victor A. McKusick - updated: 10/22/1997
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 05/03/2012
terry: 5/3/2012
ckniffin: 5/3/2012
terry: 1/13/2011
alopez: 3/18/2004
carol: 10/18/2000
carol: 4/13/2000
carol: 4/12/2000
mcapotos: 4/12/2000
mcapotos: 4/11/2000
terry: 3/2/2000
carol: 4/5/1999
terry: 3/22/1999
terry: 10/28/1997
mark: 10/27/1997
terry: 10/22/1997
carol: 6/23/1997
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
marie: 12/15/1986
*RECORD*
*FIELD* NO
112250
*FIELD* TI
#112250 DIAPHYSEAL MEDULLARY STENOSIS WITH MALIGNANT FIBROUS HISTIOCYTOMA;
DMSMFH
;;BONE DYSPLASIA WITH MEDULLARY FIBROSARCOMA; BDMF;;
read moreBONE DYSPLASIA WITH MALIGNANT FIBROUS HISTIOCYTOMA;;
MYOPATHY, LIMB-GIRDLE, WITH BONE FRAGILITY
*FIELD* TX
A number sign (#) is used with this entry because diaphyseal medullary
stenosis with malignant fibrous histiocytoma (DMSMFH) is caused by
heterozygous mutation in the MTAP gene (156540) on chromosome 9p21.
DESCRIPTION
Diaphyseal medullary stenosis with malignant fibrous histiocytoma is an
autosomal dominant bone dysplasia characterized by pathologic fractures
due to abnormal cortical growth and diaphyseal medullary stenosis. The
fractures heal poorly, and there is progressive bowing of the lower
extremities. In 2 families, affected individuals also showed a
limb-girdle myopathy, with muscle weakness and atrophy. Approximately
35% of affected individuals develop an aggressive form of bone sarcoma
consistent with malignant fibrous histiocytoma or osteosarcoma. Thus,
the disorder may be considered a tumor predisposition syndrome (summary
by Camacho-Vanegas et al., 2012).
CLINICAL FEATURES
Arnold (1973) described several generations of a Vermont and New York
kindred demonstrating multiple areas of necrosis in the diaphyses of the
large tubular bones. The radiographic appearance of this skeletal
condition resembled radiation osteitis, a highly premalignant condition;
however, no source of radiation exposure was found in this family.
Medullary fibrosarcoma, an uncommon bone tumor, was noted in 4 of the 12
affected members. Death had occurred from widespread metastases at ages
varying from 23 to 48 years. Occurrence of fibrosarcoma in idiopathic
bone infarcts (Furey et al., 1960) and in an infarct in a caisson worker
(Dorfman et al., 1966) has been reported. Camacho-Vanegas et al. (2012)
noted that 2 affected male individuals in the family reported by Arnold
(1973) died of heart disease in their early forties without other known
risk factors, and suggested that this may be a manifestation of the
disorder.
Hardcastle et al. (1986) gave follow-up information on the original
American family and reported 2 other families, one English and the other
Australian. They could find no reports of any hereditary or acquired
condition similar to that in these 3 families. They suggested that the
malignant change should be labeled 'malignant fibrous histiocytoma'
rather than fibrosarcoma because the tumors were markedly aggressive.
The malignancy occurred generally in the second to fifth decades of
life. They defined the skeletal dysplasia as a diaphyseal medullary
stenosis with overlying cortical bone thickening. The occurrence of
fracture with minimal trauma was emphasized.
Norton et al. (1996) reported a 19-year-old boy who presented with a
nontender mass on the left tibia that proved to be a pleiomorphic
spindle cell sarcoma. Radiographs of the affected leg showed extensive
diaphyseal cortical thickening and a medullary permeative pattern in the
diaphysis. Radiographs of the patient's mother and maternal grandmother
showed a similar bony dysplasia, with areas of infarction and medullary
sclerosis. The lower extremities were more affected than the upper
extremities in all 3 cases. Family history was significant for the death
of the maternal great-grandmother at age 32 from 'metastatic
osteosarcoma.' Norton et al. (1996) commented on the similarities to the
families reported by Hardcastle et al. (1986) and noted that the
malignant fibrous histiocytomas in this condition presumably begin at
the sites of infarction within the affected bone.
Henry et al. (1958) reported a Canadian family in which 6 men had
delayed healing of fractures of the long bones and later developed
myopathy. Mehta et al. (2006) provided follow-up on the family reported
by Henry et al. (1958); features of 8 living and 8 deceased family
members with the disorder were evaluated. In this family, fractures
preceded myopathy: the average age at onset of limb-girdle myopathy was
31 years, whereas that of fractures was 24 years. Fractures were
primarily of the long bones of the lower limbs and were associated with
poor healing and osteomyelitis, leading to amputation in some cases.
Serum creatine kinase was mildly increased, and alkaline phosphatase was
normal. Radiographs showed coarse trabeculation, patchy sclerosis,
cortical thickening, and narrowing of the medullary cavities of the long
bones. The findings were not consistent with Paget disease (602080).
Muscle biopsies showed nonspecific myopathic changes without necrotic
fibers, regenerating fibers, inflammatory infiltrates, or structural
abnormalities. Many affected family members had premature graying of the
hair and soft, thin skin, and 3 affected members had a clotting
disorder.
INHERITANCE
The transmission patterns in the families with DMSMFH reported by Arnold
(1973), Hardcastle et al. (1986), Norton et al. (1996), and Mehta et al.
(2006) were all consistent with autosomal dominant inheritance.
MAPPING
Martignetti et al. (1997, 1999) used microsatellite markers in a genome
screen for the gene locus in diaphyseal medullary stenosis with
malignant fibrous histiocytoma in 3 unrelated families. They linked the
syndrome to a region of approximately 3 cM on 9p22-p21, with a maximum
2-point lod score of 5.49 with marker D9S171 at recombination fraction
(theta) 0.05. This region of chromosome 9 is the site of chromosomal
abnormalities in several other malignancies and contains a number of
genes whose protein products are involved in growth regulation.
Identification of the gene responsible for this rare familial sarcoma
would be expected to define as well the cause of the more common
nonfamilial, or sporadic, form of malignant fibrous histiocytoma, a
tumor that constitutes approximately 6% of all bone cancers and is the
most frequently occurring adult soft-tissue sarcoma.
To determine whether the hereditary and sporadic forms of bone dysplasia
with malignant fibrous histiocytoma are genetically linked, Martignetti
et al. (2000) performed loss of heterozygosity (LOH) studies of the
9p22-9p21 region and found that 71% (5/7) of informative sporadic DMSMFH
specimens displayed LOH for markers within that same region. Definition
of the minimal region of LOH overlap effectively limited the DMSMFH gene
to a 2-cM region between markers D9S736 and D9S171.
By genomewide linkage analysis of the family reported by Henry et al.
(1958) and Mehta et al. (2006), Watts et al. (2005) identified a
candidate disease locus on chromosome 9p22-p21 (maximum lod score of
3.74 at marker D9S1121). Haplotype analysis refined the locus to a 15-Mb
region. Genetic analysis excluded mutations in the ADAMTSL1 (609198) and
TYRP1 (115501) genes. Watts et al. (2005) noted that the clinical
phenotype in this family and the identified locus overlap with
diaphyseal medullary stenosis with malignant fibrous histiocytoma.
MOLECULAR GENETICS
Camacho-Vanegas et al. (2012) identified 2 different heterozygous
mutations affecting exon 9 of the MTAP gene (156540.0001 and
156540.0002) in affected members of 5 unrelated families with diaphyseal
medullary stenosis with malignant fibrous histiocytoma. Four of the
families had previously been reported by Arnold (1973), Hardcastle et
al. (1986), Norton et al. (1996), and Watts et al. (2005). The mutations
were found by positional cloning and examination of putative open
reading frames within the candidate region. The analysis identified
previously unrecognized exons in the MTAP gene, including exon 9. Both
mutations affected splicing, with altered expression of MTAP isoforms.
Serum samples from 2 patients showed accumulation of methylthioadenosine
(MTA), whereas MTA was not present in serum from 3 controls. These
findings implicated a defect in MTAP enzyme activity in the patients
with mutations. DNA analysis of tumor tissue from an osteosarcoma of 1
patient showed homozygosity for the mutation with loss of heterozygosity
of the wildtype allele. The findings of the study suggested that MTAP
can also act as a tumor suppressor gene.
*FIELD* RF
1. Arnold, W. H.: Hereditary bone dysplasia with sarcomatous degeneration. Ann.
Intern. Med. 78: 902-906, 1973.
2. Camacho-Vanegas, O.; Camacho, S. C.; Till, J.; Miranda-Lorenzo,
I.; Terzo, E.; Ramirez, M. C.; Schramm, V.; Cordovano, G.; Watts,
G.; Mehta, S.; Kimonis, V.; Hoch, B.; Philibert, K. D.; Raabe, C.
A.; Bishop, D. F.; Glucksman, M. J.; Martignetti, J. A.: Primate
genome gain and loss: a bone dysplasia, muscular dystrophy, and bone
cancer syndrome resulting from mutated retroviral-derived MTAP transcripts. Am.
J. Hum. Genet. 90: 614-627, 2012.
3. Dorfman, H. D.; Norman, A.; Wolff, H.: Fibrosarcoma complicating
bone infarction in a caisson worker. J. Bone Joint Surg. Am. 48:
528-532, 1966.
4. Furey, J. G.; Ferrer-Torells, M.; Reagan, J. W.: Fibrosarcoma
arising at the site of bone infarcts. J. Bone Joint Surg. Am. 42:
802-810, 1960.
5. Hardcastle, P.; Nade, S.; Arnold, W.: Hereditary bone dysplasia
with malignant change: report of three families. J. Bone Joint Surg.
Am. 68: 1079-1089, 1986.
6. Henry, E. W.; Auckland, N. L.; McIntosh, H. W.; Starr, D. E.:
Abnormality of the long bones and progressive muscular dystrophy in
a family. Canad. Med. Assoc. J. 78: 331-336, 1958.
7. Martignetti, J. A.; Desnick, R. J.; Aliprandis, E.; Norton, K.
I.; Hardcastle, P.; Nade, S.; Gelb, B. D.: Diaphyseal medullary stenosis
with malignant fibrous histiocytoma: a hereditary bone dysplasia/cancer
syndrome maps to 9p21-22. Am. J. Hum. Genet. 64: 801-807, 1999.
8. Martignetti, J. A.; Desnick, R. J.; Norton, K.; Hardcastle, P.;
Nade, S.; Gelb, B. D.: Genetic linkage of hereditary bone dysplasia
with malignant changes to chromosome 9p21-22. (Abstract) Am. J. Hum.
Genet. 61 (suppl.): A284 only, 1997.
9. Martignetti, J. A.; Gelb, B. D.; Pierce, H.; Picci, P.; Desnick,
R. J.: Malignant fibrous histiocytoma: inherited and sporadic forms
have loss of heterozygosity at chromosome bands 9p21-p22--evidence
for a common genetic defect. Genes Chromosomes Cancer 27: 191-195,
2000.
10. Mehta, S. G.; Watts, G. D. J.; McGillivray, B.; Mumm, S.; Hamilton,
S. J.; Ramdeen, S.; Novack, D.; Briggs, C.; Whyte, M. P.; Kimonis,
V. E.: Manifestations in a family with autosomal dominant bone fragility
and limb-girdle myopathy. Am. J. Med. Genet. 140A: 322-330, 2006.
11. Norton, K. I.; Wagreich, J. M.; Granowetter, L.; Martignetti,
J. A.: Diaphyseal medullary stenosis (sclerosis) with bone malignancy
(malignant fibrous histiocytoma): Hardcastle syndrome. Pediat. Radiol. 26:
675-677, 1996.
12. Watts, G. D. J.; Mehta, S. G.; Zhao, C.; Ramdeen, S.; Hamilton,
S. J.; Novack, D. V.; Mumm, S.; Whyte, M. P.; McGillivray, B.; Kimonis,
V. E.: Mapping autosomal dominant progressive limb-girdle myopathy
with bone fragility to chromosome 9p21-p22: a novel locus for a musculoskeletal
syndrome. Hum. Genet. 118: 508-514, 2005.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Presenile cataracts
SKELETAL:
Osteopenia;
Radiolucency of the bones;
[Limbs];
Bony dysplasia;
Pathologic fractures of the long bones;
Osteomyelitis leading to amputation due to slow healing fractures;
Patchy sclerotic changes to the long bones;
Coarse, sclerotic trabeculae;
Diaphyseal cortical thickening;
Diaphyseal medullary stenosis;
Metaphyseal striations;
Necrosis in large tubular bone diaphyses;
Narrow medullary cavities;
Marrow necrosis;
Marrow infarctions;
Bowing of the lower extremities
SKIN, NAILS, HAIR:
[Skin];
Soft, thin skin (1 family);
Easy bruising (1 family);
[Hair];
Premature graying (1 family)
MUSCLE, SOFT TISSUE:
Limb-girdle muscle weakness (2 families);
Proximal muscle weakness;
Proximal and distal muscle atrophy;
Distal limb muscle weakness occurs later;
Myopathic changes seen on EMG and muscle biopsy
NEOPLASIA:
Malignant fibrous histiocytoma (in about 35% of patients);
Osteosarcoma;
Fibrosarcoma
LABORATORY ABNORMALITIES:
Serum alkaline phosphatase normal or mildly increased;
Serum creatine kinase normal or mildly increased
MISCELLANEOUS:
Mean age at onset of bone fractures, 24 years;
Mean age at onset of proximal muscle weakness, 31 years;
Progressive disorder;
Not all patients have a myopathy;
Most become wheelchair-bound late in life
MOLECULAR BASIS:
Caused by mutation in the methylthioadenosine phosphorylase gene (MTAP,
156540.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 5/3/2012
*FIELD* CD
John F. Jackson: 6/15/1996
*FIELD* ED
joanna: 05/16/2012
joanna: 5/4/2012
ckniffin: 5/3/2012
joanna: 10/26/2006
ckniffin: 2/28/2006
*FIELD* CN
Cassandra L. Kniffin - updated: 5/3/2012
Victor A. McKusick - updated: 3/2/2000
Victor A. McKusick - updated: 3/22/1999
Victor A. McKusick - updated: 10/22/1997
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 05/03/2012
terry: 5/3/2012
ckniffin: 5/3/2012
terry: 1/13/2011
alopez: 3/18/2004
carol: 10/18/2000
carol: 4/13/2000
carol: 4/12/2000
mcapotos: 4/12/2000
mcapotos: 4/11/2000
terry: 3/2/2000
carol: 4/5/1999
terry: 3/22/1999
terry: 10/28/1997
mark: 10/27/1997
terry: 10/22/1997
carol: 6/23/1997
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
marie: 12/15/1986
MIM
156540
*RECORD*
*FIELD* NO
156540
*FIELD* TI
*156540 METHYLTHIOADENOSINE PHOSPHORYLASE; MTAP
;;MeSAdo PHOSPHORYLASE; MSAP
*FIELD* TX
read more
DESCRIPTION
The MTAP gene encodes methylthioadenosine phosphorylase (EC 24.2.28), a
homotrimeric-subunit enzyme that plays a major role in polyamine
metabolism and is important for the salvage of both adenine and
methionine. For example, as much as 97% of the endogenous adenine
produced by human lymphoblasts in culture is formed by catabolism of
methylthioadenosine (MeSAdo) by the phosphorylase. MeSAdo, a by-product
of the synthesis of the polyamines spermidine and spermine, potently
inhibits polyamine aminopropyltransferase reactions if not removed by
the above phosphorylase reaction. MeSAdo phosphorylase is abundant in
normal cells and tissues but lacking from many human and murine
malignant cell lines and from some human leukemias in vivo (summary by
Carrera et al., 1984; Camacho-Vanegas et al., 2012).
CLONING
Olopade et al. (1995) constructed a long-range physical map of 2.8 Mb
from chromosome 9p21, where the MTAP gene is located, using overlapping
YAC and cosmid clones. Sequence analysis of a 2.5-kb cDNA clone isolated
from a CpG island located in the contig between the IFN genes (see IFNA;
147660) and CDKN2 (600160) revealed a predicted ORF for MTAP of 283
amino acids followed by 1,302-bp of 3-prime UTR. The MTAP gene is
evolutionarily conserved and shows significant amino acid homology to
mouse and human purine nucleotide phosphorylases.
Using RT-PCR, Burdon et al. (2011) demonstrated expression of MTAP in
human ocular tissues, including in the iris, ciliary body, retina, and
optic nerve.
Camacho-Vanegas et al. (2012) identified 6 additional transcripts of the
MTAP gene that used previously uncharacterized exons. None of these 6
additional isoforms contained the archetypal terminal exon 8, and all
affected the C terminus of the protein product in different ways. Four
contained either a short or long form of exon 9, and 4 contained a
unique sequence containing 2 additional downstream exons, 10 and 11. The
alternative splice site variants were named on the basis of their
electrophoretic mobility: MTAP v1 (exons 1-7 and 9S-11), v2 (exons 1-7
and 9L), v3 (exons 1-7, 10, and 11), v4 (exons 1-6 and 9S-11), v5 (exons
1-6 and 9L), and v6 (exons 1-6, 10, and 11). Splice variants 1-3
contained the wildtype exon 7 sequence; variants 4-6 did not. The
variants were all translated and able to interact with archetypal MTAP.
However, only isoforms v1, v2, and v3 demonstrated MTAP activity; v4,
v5, and v6 showed shorter half-lives and had no detectable MTAP
activity. Molecular modeling suggested that MTAP is a trimer with
heterologous assembly of different subunits composed of archetype and
splice variants.
GENE STRUCTURE
Nobori et al. (1996) determined that the MTAP gene contains 8 exons.
Camacho-Vanegas et al. (2012) identified 3 additional exons of MTAP,
which they termed 9, 10, and 11. Sequence analysis of the 3 terminal
exons showed that exons 9 and 10 shared high homology with different
primate-specific retroviral sequences that are known to have integrated
multiple times into different chromosomes throughout the genome.
MAPPING
Carrera et al. (1984) studied hybrids between MeSAdo
phosphorylase-deficient mouse L cells and human fibroblasts to show that
the MTAP gene is located in the 9pter-q12 segment.
As indicated by the findings of Olopade et al. (1992), the MTAP locus is
centromeric to the cluster of interferon genes (e.g., 147640). Thus, the
likely location of MTAP is 9p21.
Nobori et al. (1996) cloned the MTAP gene and constructed a topologic
map of the 9p21 region using YAC clones, pulsed-field gel
electrophoresis, and sequence tagged-site PCR. They found that the gene
order on chromosome 9p21, starting from the centromeric end, is p15
(600431)--p16 (600160)--MTAP--IFNA--IFNB (147640).
Kadariya et al. (2009) stated that the mouse Mtap gene maps to
chromosome 4.
GENE FUNCTION
Ragione et al. (1996) expressed recombinant human MTAP and showed it to
have the expected enzymatic properties.
The MTAP enzyme is missing in malignant cells in cases of lymphomatous
acute lymphoblastic leukemia (247640); many of these cases have
abnormality of 9p22-p21 (Chilcote et al., 1985).
Nobori et al. (1996) found that of 23 malignant cell lines deficient in
MTAP, all but 1 had complete or partial deletion of the MTAP gene. They
also found partial or total deletion of the MTAP gene in primary T-cell
acute lymphoblastic leukemias. In both cases, the deletion breakpoint of
partial deletions occurred within intron 4. Nobori et al. (1996)
suggested that MTAP deficiency in malignancy results from total or
partial deletion of the MTAP gene, which is closely linked to the p16
and p15 genes. They noted that both p16 and p15 are homozygously deleted
in many different malignant cell lines as well as in acute leukemias.
MOLECULAR GENETICS
Camacho-Vanegas et al. (2012) identified 2 different heterozygous
mutations affecting exon 9 of the MTAP gene (156540.0001 and
156540.0002) in affected members of 5 unrelated families with diaphyseal
medullary stenosis with malignant fibrous histiocytoma (DMSMFH; 112250).
Four of the families had previously been reported by Arnold (1973),
Hardcastle et al. (1986), Norton et al. (1996), and Watts et al. (2005).
The mutations were found by positional cloning and examination of
putative open reading frames within the candidate region. The analysis
identified previously unrecognized exons in the MTAP gene, including
exon 9. Both mutations affected splicing, with altered expression of
MTAP isoforms. Serum samples from 2 patients showed accumulation of
methylthioadenosine (MTA), whereas MTA was not present in serum from 3
controls. These findings implicated a defect in MTAP enzyme activity in
patients with mutations. DNA analysis of tumor tissue from an
osteosarcoma of 1 patient showed homozygosity for the mutation with loss
of heterozygosity (LOH) of the wildtype allele. The findings of the
study suggested that MTAP can also act as a tumor suppressor gene.
EVOLUTION
Camacho-Vanegas et al. (2012) identified 3 previously unrecognized exons
of MTAP, which they termed 9, 10, and 11. Sequence analysis of these 3
terminal exons showed that exons 9 and 10 share high homology with
different primate-specific retroviral sequences that are known to have
integrated multiple times into different chromosomes throughout the
genome. Exon 9 arose from part of a MER50I element, and exon 10 arose
from part of a THE1A element, 1 of several families of primate-specific
long terminal repeat (LTR) retrotransposons. Sequencing of PCR amplicons
covering exon 9 in great apes and Old and New World monkeys indicated
that the MER50I remnant was integrated over 40 million years ago into
the lineage leading to anthropoid primates.
ANIMAL MODEL
After demonstrating by FISH that the chromosome 9 breakpoint in a deaf
patient with a balanced translocation t(8;9)(q12.1;p21.3) disrupted the
MTAP gene, Williamson et al. (2007) created a mouse model for MTAP
deficiency and found that Mtap +/- mice had no significant pathology;
specifically, no hearing loss was observed. Mtap-deficient mice were
embryonic lethal.
Independently, Kadariya et al. (2009) found that homozygous Mtap
deletion in mice was embryonic lethal. Mtap +/- mice appeared normal for
the first year of life, and they had normal serum amino acid profiles.
However, Mtap +/- mice had reduced life span compared with wildtype
littermates. Necropsy showed marked splenomegaly, often with enlargement
of the liver and thymus, and severe lymphoproliferative disease
resembling T-cell lymphoma.
*FIELD* AV
.0001
DIAPHYSEAL MEDULLARY STENOSIS WITH MALIGNANT FIBROUS HISTIOCYTOMA
MTAP, 885A-G, ARG100ARG
In affected members of 3 unrelated families with diaphyseal medullary
stenosis with malignant fibrous histiocytoma (DMSMFH; 112250),
Camacho-Vanegas et al. (2012) identified a heterozygous 885A-G
transition in exon 9 of the MTAP gene, resulting in a synonymous
arg100-to-arg (R100R) substitution. The mutation was not found in 1,000
control chromosomes. Two of the families had previously been reported by
Arnold (1973) and Norton et al. (1996). The 885A-G transition was
predicted to abolish an exonic splicing enhancer sequence, and in vitro
functional expression studies using minigene constructs demonstrated
that the mutation resulted in markedly decreased (70%) expression of
exon-9-containing transcripts. There was also an increase in expression
of the 2 isoforms lacking exon 9. The dysregulated expression pattern
was also observed in patient-derived tissues.
.0002
DIAPHYSEAL MEDULLARY STENOSIS WITH MALIGNANT FIBROUS HISTIOCYTOMA
MTAP, IVS9AS, A-G, -2
In affected members of 2 unrelated families with DMSMFH (112250),
Camacho-Vanegas et al. (2012) identified a heterozygous A-to-G
transition in intron 9 of the MTAP gene (IVS9-2A-G). The mutation was
not found in 1,000 control chromosomes. One of the families was of
Australian origin and had previously been reported by Hardcastle et al.
(1986); the other family had been reported by Henry et al. (1958), Watts
et al. (2005), and Mehta et al. (2006). The A-to-G transition was
predicted to result in the loss of an acceptor splice site, and in vitro
functional expression studies using minigene constructs demonstrated
that the mutation ablated expression of all isoforms containing exon 9
and increased the expression of the archetypal isoform ending at exon 8
as well as an increase in the isoforms lacking exon 9. In addition, the
first 3 amino acids were lacking from both 9S isoforms. The dysregulated
expression pattern was also observed in patient-derived tissues.
*FIELD* SA
Williams-Ashman et al. (1982)
*FIELD* RF
1. Arnold, W. H.: Hereditary bone dysplasia with sarcomatous degeneration. Ann.
Intern. Med. 78: 902-906, 1973.
2. Burdon, K. P.; Macgregor, S.; Hewitt, A. W.; Sharma, S.; Chidlow,
G.; Mills, R. A.; Danoy, P.; Casson, R.; Viswanathan, A. C.; Liu,
J. Z.; Landers, J.; Henders, A. K.; and 13 others: Genome-wide association
study identifies susceptibility loci for open angle glaucoma at TMCO1
and CDKN2B-AS1. Nature Genet. 43: 574-578, 2011.
3. Camacho-Vanegas, O.; Camacho, S. C.; Till, J.; Miranda-Lorenzo,
I.; Terzo, E.; Ramirez, M. C.; Schramm, V.; Cordovano, G.; Watts,
G.; Mehta, S.; Kimonis, V.; Hoch, B.; Philibert, K. D.; Raabe, C.
A.; Bishop, D. F.; Glucksman, M. J.; Martignetti, J. A.: Primate
genome gain and loss: a bone dysplasia, muscular dystrophy, and bone
cancer syndrome resulting from mutated retroviral-derived MTAP transcripts. Am.
J. Hum. Genet. 90: 614-627, 2012.
4. Carrera, C. J.; Eddy, R. L.; Shows, T. B.; Carson, D. A.: Assignment
of the gene for methylthioadenosine phosphorylase to human chromosome
9 by mouse-human somatic cell hybridization. Proc. Nat. Acad. Sci. 81:
2665-2668, 1984.
5. Chilcote, R. R.; Brown, E.; Rowley, J. D.: Lymphoblastic leukemia
with lymphomatous features associated with abnormalities of the short
arm of chromosome 9. New Eng. J. Med. 313: 286-291, 1985.
6. Hardcastle, P.; Nade, S.; Arnold, W.: Hereditary bone dysplasia
with malignant change: report of three families. J. Bone Joint Surg.
Am. 68: 1079-1089, 1986.
7. Henry, E. W.; Auckland, N. L.; McIntosh, H. W.; Starr, D. E.:
Abnormality of the long bones and progressive muscular dystrophy in
a family. Canad. Med. Assoc. J. 78: 331-336, 1958.
8. Kadariya, Y.; Yin, B.; Tang, B.; Shinton, S. A.; Quinlivan, E.
P.; Hua, X.; Klein-Szanto, A.; Al-Saleem, T. I.; Bassing, C. H.; Hardy,
R. R.; Kruger, W. D.: Mice heterozygous for germ-line mutations in
methylthioadenosine phosphorylase (MTAP) die prematurely of T-cell
lymphoma. Cancer Res. 69: 5961-5969, 2009.
9. Mehta, S. G.; Watts, G. D. J.; McGillivray, B.; Mumm, S.; Hamilton,
S. J.; Ramdeen, S.; Novack, D.; Briggs, C.; Whyte, M. P.; Kimonis,
V. E.: Manifestations in a family with autosomal dominant bone fragility
and limb-girdle myopathy. Am. J. Med. Genet. 140A: 322-330, 2006.
10. Nobori, T.; Takabayashi, K.; Tran, P.; Orvis, L.; Batova, A.;
Yu, A. L.; Carson, D. A.: Genomic cloning of methylthioadenosine
phosphorylase: a purine metabolic enzyme deficient in multiple different
cancers. Proc. Nat. Acad. Sci. 93: 6203-6208, 1996.
11. Norton, K. I.; Wagreich, J. M.; Granowetter, L.; Martignetti,
J. A.: Diaphyseal medullary stenosis (sclerosis) with bone malignancy
(malignant fibrous histiocytoma): Hardcastle syndrome. Pediat. Radiol. 26:
675-677, 1996.
12. Olopade, O. I.; Jenkins, R. B.; Ransom, D. T.; Malik, K.; Pomykala,
H.; Nobori, T.; Cowan, J. M.; Rowley, J. D.; Diaz, M. O.: Molecular
analysis of deletions of the short arm of chromosome 9 in human gliomas. Cancer
Res. 52: 2523-2529, 1992.
13. Olopade, O. I.; Pomykala, H. M.; Hagos, F.; Sveen, L. W.; Espinosa,
R., III; Dreyling, M. H.; Gursky, S.; Stadler, W. M.; Le Beau, M.
M.; Bohlander, S. K.: Construction of a 2.8-megabase yeast artificial
chromosome contig and cloning of the human methylthioadenosine phosphorylase
gene from the tumor suppressor region on 9p21. Proc. Nat. Acad. Sci. 92:
6489-6493, 1995.
14. Ragione, F. D.; Takabayashi, K.; Mastropietro, S.; Mercurio, C.;
Oliva, A.; Russo, G. L.; Pietra, V. D.; Borriello, A.; Nobori, T.;
Carson, D. A.; Zappia, V.: Purification and characterization of recombinant
human 5-prime-methylthioadenosine phosphorylase: definite identification
of coding cDNA. Biochem. Biophys. Res. Commun. 223: 514-519, 1996.
15. Watts, G. D. J.; Mehta, S. G.; Zhao, C.; Ramdeen, S.; Hamilton,
S. J.; Novack, D. V.; Mumm, S.; Whyte, M. P.; McGillivray, B.; Kimonis,
V. E.: Mapping autosomal dominant progressive limb-girdle myopathy
with bone fragility to chromosome 9p21-p22: a novel locus for a musculoskeletal
syndrome. Hum. Genet. 118: 508-514, 2005.
16. Williams-Ashman, H. G.; Seidenfeld, J.; Galletti, P.: Trends
in the biochemical pharmacology of 5-prime-deoxy-5-prime-methylthioadenosine. Biochem.
Pharm. 31: 277-288, 1982.
17. Williamson, R. E.; Darrow, K. N.; Michaud, S.; Jacobs, J. S.;
Jones, M. C.; Eberl, D. F.; Maas, R. L.; Liberman, M. C.; Morton,
C. C.: Methylthioadenosine phosphorylase (MTAP) in hearing: gene
disruption by chromosomal rearrangement in a hearing impaired individual
and model organism analysis. Am. J. Med. Genet. 143A: 1630-1639,
2007.
*FIELD* CN
Cassandra L. Kniffin - updated: 5/3/2012
Marla J. F. O'Neill - updated: 12/6/2011
Patricia A. Hartz - updated: 11/2/2010
Marla J. F. O'Neill - updated: 5/30/2008
Alan F. Scott - updated: 9/25/1996
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 05/03/2012
terry: 5/3/2012
ckniffin: 5/3/2012
terry: 12/6/2011
mgross: 11/3/2010
terry: 11/2/2010
carol: 6/3/2008
terry: 5/30/2008
mgross: 4/8/1999
terry: 9/25/1996
mark: 9/25/1996
terry: 8/28/1996
terry: 7/16/1996
mark: 7/24/1995
carol: 6/6/1994
carol: 7/8/1992
supermim: 3/16/1992
carol: 6/11/1990
supermim: 3/20/1990
*RECORD*
*FIELD* NO
156540
*FIELD* TI
*156540 METHYLTHIOADENOSINE PHOSPHORYLASE; MTAP
;;MeSAdo PHOSPHORYLASE; MSAP
*FIELD* TX
read more
DESCRIPTION
The MTAP gene encodes methylthioadenosine phosphorylase (EC 24.2.28), a
homotrimeric-subunit enzyme that plays a major role in polyamine
metabolism and is important for the salvage of both adenine and
methionine. For example, as much as 97% of the endogenous adenine
produced by human lymphoblasts in culture is formed by catabolism of
methylthioadenosine (MeSAdo) by the phosphorylase. MeSAdo, a by-product
of the synthesis of the polyamines spermidine and spermine, potently
inhibits polyamine aminopropyltransferase reactions if not removed by
the above phosphorylase reaction. MeSAdo phosphorylase is abundant in
normal cells and tissues but lacking from many human and murine
malignant cell lines and from some human leukemias in vivo (summary by
Carrera et al., 1984; Camacho-Vanegas et al., 2012).
CLONING
Olopade et al. (1995) constructed a long-range physical map of 2.8 Mb
from chromosome 9p21, where the MTAP gene is located, using overlapping
YAC and cosmid clones. Sequence analysis of a 2.5-kb cDNA clone isolated
from a CpG island located in the contig between the IFN genes (see IFNA;
147660) and CDKN2 (600160) revealed a predicted ORF for MTAP of 283
amino acids followed by 1,302-bp of 3-prime UTR. The MTAP gene is
evolutionarily conserved and shows significant amino acid homology to
mouse and human purine nucleotide phosphorylases.
Using RT-PCR, Burdon et al. (2011) demonstrated expression of MTAP in
human ocular tissues, including in the iris, ciliary body, retina, and
optic nerve.
Camacho-Vanegas et al. (2012) identified 6 additional transcripts of the
MTAP gene that used previously uncharacterized exons. None of these 6
additional isoforms contained the archetypal terminal exon 8, and all
affected the C terminus of the protein product in different ways. Four
contained either a short or long form of exon 9, and 4 contained a
unique sequence containing 2 additional downstream exons, 10 and 11. The
alternative splice site variants were named on the basis of their
electrophoretic mobility: MTAP v1 (exons 1-7 and 9S-11), v2 (exons 1-7
and 9L), v3 (exons 1-7, 10, and 11), v4 (exons 1-6 and 9S-11), v5 (exons
1-6 and 9L), and v6 (exons 1-6, 10, and 11). Splice variants 1-3
contained the wildtype exon 7 sequence; variants 4-6 did not. The
variants were all translated and able to interact with archetypal MTAP.
However, only isoforms v1, v2, and v3 demonstrated MTAP activity; v4,
v5, and v6 showed shorter half-lives and had no detectable MTAP
activity. Molecular modeling suggested that MTAP is a trimer with
heterologous assembly of different subunits composed of archetype and
splice variants.
GENE STRUCTURE
Nobori et al. (1996) determined that the MTAP gene contains 8 exons.
Camacho-Vanegas et al. (2012) identified 3 additional exons of MTAP,
which they termed 9, 10, and 11. Sequence analysis of the 3 terminal
exons showed that exons 9 and 10 shared high homology with different
primate-specific retroviral sequences that are known to have integrated
multiple times into different chromosomes throughout the genome.
MAPPING
Carrera et al. (1984) studied hybrids between MeSAdo
phosphorylase-deficient mouse L cells and human fibroblasts to show that
the MTAP gene is located in the 9pter-q12 segment.
As indicated by the findings of Olopade et al. (1992), the MTAP locus is
centromeric to the cluster of interferon genes (e.g., 147640). Thus, the
likely location of MTAP is 9p21.
Nobori et al. (1996) cloned the MTAP gene and constructed a topologic
map of the 9p21 region using YAC clones, pulsed-field gel
electrophoresis, and sequence tagged-site PCR. They found that the gene
order on chromosome 9p21, starting from the centromeric end, is p15
(600431)--p16 (600160)--MTAP--IFNA--IFNB (147640).
Kadariya et al. (2009) stated that the mouse Mtap gene maps to
chromosome 4.
GENE FUNCTION
Ragione et al. (1996) expressed recombinant human MTAP and showed it to
have the expected enzymatic properties.
The MTAP enzyme is missing in malignant cells in cases of lymphomatous
acute lymphoblastic leukemia (247640); many of these cases have
abnormality of 9p22-p21 (Chilcote et al., 1985).
Nobori et al. (1996) found that of 23 malignant cell lines deficient in
MTAP, all but 1 had complete or partial deletion of the MTAP gene. They
also found partial or total deletion of the MTAP gene in primary T-cell
acute lymphoblastic leukemias. In both cases, the deletion breakpoint of
partial deletions occurred within intron 4. Nobori et al. (1996)
suggested that MTAP deficiency in malignancy results from total or
partial deletion of the MTAP gene, which is closely linked to the p16
and p15 genes. They noted that both p16 and p15 are homozygously deleted
in many different malignant cell lines as well as in acute leukemias.
MOLECULAR GENETICS
Camacho-Vanegas et al. (2012) identified 2 different heterozygous
mutations affecting exon 9 of the MTAP gene (156540.0001 and
156540.0002) in affected members of 5 unrelated families with diaphyseal
medullary stenosis with malignant fibrous histiocytoma (DMSMFH; 112250).
Four of the families had previously been reported by Arnold (1973),
Hardcastle et al. (1986), Norton et al. (1996), and Watts et al. (2005).
The mutations were found by positional cloning and examination of
putative open reading frames within the candidate region. The analysis
identified previously unrecognized exons in the MTAP gene, including
exon 9. Both mutations affected splicing, with altered expression of
MTAP isoforms. Serum samples from 2 patients showed accumulation of
methylthioadenosine (MTA), whereas MTA was not present in serum from 3
controls. These findings implicated a defect in MTAP enzyme activity in
patients with mutations. DNA analysis of tumor tissue from an
osteosarcoma of 1 patient showed homozygosity for the mutation with loss
of heterozygosity (LOH) of the wildtype allele. The findings of the
study suggested that MTAP can also act as a tumor suppressor gene.
EVOLUTION
Camacho-Vanegas et al. (2012) identified 3 previously unrecognized exons
of MTAP, which they termed 9, 10, and 11. Sequence analysis of these 3
terminal exons showed that exons 9 and 10 share high homology with
different primate-specific retroviral sequences that are known to have
integrated multiple times into different chromosomes throughout the
genome. Exon 9 arose from part of a MER50I element, and exon 10 arose
from part of a THE1A element, 1 of several families of primate-specific
long terminal repeat (LTR) retrotransposons. Sequencing of PCR amplicons
covering exon 9 in great apes and Old and New World monkeys indicated
that the MER50I remnant was integrated over 40 million years ago into
the lineage leading to anthropoid primates.
ANIMAL MODEL
After demonstrating by FISH that the chromosome 9 breakpoint in a deaf
patient with a balanced translocation t(8;9)(q12.1;p21.3) disrupted the
MTAP gene, Williamson et al. (2007) created a mouse model for MTAP
deficiency and found that Mtap +/- mice had no significant pathology;
specifically, no hearing loss was observed. Mtap-deficient mice were
embryonic lethal.
Independently, Kadariya et al. (2009) found that homozygous Mtap
deletion in mice was embryonic lethal. Mtap +/- mice appeared normal for
the first year of life, and they had normal serum amino acid profiles.
However, Mtap +/- mice had reduced life span compared with wildtype
littermates. Necropsy showed marked splenomegaly, often with enlargement
of the liver and thymus, and severe lymphoproliferative disease
resembling T-cell lymphoma.
*FIELD* AV
.0001
DIAPHYSEAL MEDULLARY STENOSIS WITH MALIGNANT FIBROUS HISTIOCYTOMA
MTAP, 885A-G, ARG100ARG
In affected members of 3 unrelated families with diaphyseal medullary
stenosis with malignant fibrous histiocytoma (DMSMFH; 112250),
Camacho-Vanegas et al. (2012) identified a heterozygous 885A-G
transition in exon 9 of the MTAP gene, resulting in a synonymous
arg100-to-arg (R100R) substitution. The mutation was not found in 1,000
control chromosomes. Two of the families had previously been reported by
Arnold (1973) and Norton et al. (1996). The 885A-G transition was
predicted to abolish an exonic splicing enhancer sequence, and in vitro
functional expression studies using minigene constructs demonstrated
that the mutation resulted in markedly decreased (70%) expression of
exon-9-containing transcripts. There was also an increase in expression
of the 2 isoforms lacking exon 9. The dysregulated expression pattern
was also observed in patient-derived tissues.
.0002
DIAPHYSEAL MEDULLARY STENOSIS WITH MALIGNANT FIBROUS HISTIOCYTOMA
MTAP, IVS9AS, A-G, -2
In affected members of 2 unrelated families with DMSMFH (112250),
Camacho-Vanegas et al. (2012) identified a heterozygous A-to-G
transition in intron 9 of the MTAP gene (IVS9-2A-G). The mutation was
not found in 1,000 control chromosomes. One of the families was of
Australian origin and had previously been reported by Hardcastle et al.
(1986); the other family had been reported by Henry et al. (1958), Watts
et al. (2005), and Mehta et al. (2006). The A-to-G transition was
predicted to result in the loss of an acceptor splice site, and in vitro
functional expression studies using minigene constructs demonstrated
that the mutation ablated expression of all isoforms containing exon 9
and increased the expression of the archetypal isoform ending at exon 8
as well as an increase in the isoforms lacking exon 9. In addition, the
first 3 amino acids were lacking from both 9S isoforms. The dysregulated
expression pattern was also observed in patient-derived tissues.
*FIELD* SA
Williams-Ashman et al. (1982)
*FIELD* RF
1. Arnold, W. H.: Hereditary bone dysplasia with sarcomatous degeneration. Ann.
Intern. Med. 78: 902-906, 1973.
2. Burdon, K. P.; Macgregor, S.; Hewitt, A. W.; Sharma, S.; Chidlow,
G.; Mills, R. A.; Danoy, P.; Casson, R.; Viswanathan, A. C.; Liu,
J. Z.; Landers, J.; Henders, A. K.; and 13 others: Genome-wide association
study identifies susceptibility loci for open angle glaucoma at TMCO1
and CDKN2B-AS1. Nature Genet. 43: 574-578, 2011.
3. Camacho-Vanegas, O.; Camacho, S. C.; Till, J.; Miranda-Lorenzo,
I.; Terzo, E.; Ramirez, M. C.; Schramm, V.; Cordovano, G.; Watts,
G.; Mehta, S.; Kimonis, V.; Hoch, B.; Philibert, K. D.; Raabe, C.
A.; Bishop, D. F.; Glucksman, M. J.; Martignetti, J. A.: Primate
genome gain and loss: a bone dysplasia, muscular dystrophy, and bone
cancer syndrome resulting from mutated retroviral-derived MTAP transcripts. Am.
J. Hum. Genet. 90: 614-627, 2012.
4. Carrera, C. J.; Eddy, R. L.; Shows, T. B.; Carson, D. A.: Assignment
of the gene for methylthioadenosine phosphorylase to human chromosome
9 by mouse-human somatic cell hybridization. Proc. Nat. Acad. Sci. 81:
2665-2668, 1984.
5. Chilcote, R. R.; Brown, E.; Rowley, J. D.: Lymphoblastic leukemia
with lymphomatous features associated with abnormalities of the short
arm of chromosome 9. New Eng. J. Med. 313: 286-291, 1985.
6. Hardcastle, P.; Nade, S.; Arnold, W.: Hereditary bone dysplasia
with malignant change: report of three families. J. Bone Joint Surg.
Am. 68: 1079-1089, 1986.
7. Henry, E. W.; Auckland, N. L.; McIntosh, H. W.; Starr, D. E.:
Abnormality of the long bones and progressive muscular dystrophy in
a family. Canad. Med. Assoc. J. 78: 331-336, 1958.
8. Kadariya, Y.; Yin, B.; Tang, B.; Shinton, S. A.; Quinlivan, E.
P.; Hua, X.; Klein-Szanto, A.; Al-Saleem, T. I.; Bassing, C. H.; Hardy,
R. R.; Kruger, W. D.: Mice heterozygous for germ-line mutations in
methylthioadenosine phosphorylase (MTAP) die prematurely of T-cell
lymphoma. Cancer Res. 69: 5961-5969, 2009.
9. Mehta, S. G.; Watts, G. D. J.; McGillivray, B.; Mumm, S.; Hamilton,
S. J.; Ramdeen, S.; Novack, D.; Briggs, C.; Whyte, M. P.; Kimonis,
V. E.: Manifestations in a family with autosomal dominant bone fragility
and limb-girdle myopathy. Am. J. Med. Genet. 140A: 322-330, 2006.
10. Nobori, T.; Takabayashi, K.; Tran, P.; Orvis, L.; Batova, A.;
Yu, A. L.; Carson, D. A.: Genomic cloning of methylthioadenosine
phosphorylase: a purine metabolic enzyme deficient in multiple different
cancers. Proc. Nat. Acad. Sci. 93: 6203-6208, 1996.
11. Norton, K. I.; Wagreich, J. M.; Granowetter, L.; Martignetti,
J. A.: Diaphyseal medullary stenosis (sclerosis) with bone malignancy
(malignant fibrous histiocytoma): Hardcastle syndrome. Pediat. Radiol. 26:
675-677, 1996.
12. Olopade, O. I.; Jenkins, R. B.; Ransom, D. T.; Malik, K.; Pomykala,
H.; Nobori, T.; Cowan, J. M.; Rowley, J. D.; Diaz, M. O.: Molecular
analysis of deletions of the short arm of chromosome 9 in human gliomas. Cancer
Res. 52: 2523-2529, 1992.
13. Olopade, O. I.; Pomykala, H. M.; Hagos, F.; Sveen, L. W.; Espinosa,
R., III; Dreyling, M. H.; Gursky, S.; Stadler, W. M.; Le Beau, M.
M.; Bohlander, S. K.: Construction of a 2.8-megabase yeast artificial
chromosome contig and cloning of the human methylthioadenosine phosphorylase
gene from the tumor suppressor region on 9p21. Proc. Nat. Acad. Sci. 92:
6489-6493, 1995.
14. Ragione, F. D.; Takabayashi, K.; Mastropietro, S.; Mercurio, C.;
Oliva, A.; Russo, G. L.; Pietra, V. D.; Borriello, A.; Nobori, T.;
Carson, D. A.; Zappia, V.: Purification and characterization of recombinant
human 5-prime-methylthioadenosine phosphorylase: definite identification
of coding cDNA. Biochem. Biophys. Res. Commun. 223: 514-519, 1996.
15. Watts, G. D. J.; Mehta, S. G.; Zhao, C.; Ramdeen, S.; Hamilton,
S. J.; Novack, D. V.; Mumm, S.; Whyte, M. P.; McGillivray, B.; Kimonis,
V. E.: Mapping autosomal dominant progressive limb-girdle myopathy
with bone fragility to chromosome 9p21-p22: a novel locus for a musculoskeletal
syndrome. Hum. Genet. 118: 508-514, 2005.
16. Williams-Ashman, H. G.; Seidenfeld, J.; Galletti, P.: Trends
in the biochemical pharmacology of 5-prime-deoxy-5-prime-methylthioadenosine. Biochem.
Pharm. 31: 277-288, 1982.
17. Williamson, R. E.; Darrow, K. N.; Michaud, S.; Jacobs, J. S.;
Jones, M. C.; Eberl, D. F.; Maas, R. L.; Liberman, M. C.; Morton,
C. C.: Methylthioadenosine phosphorylase (MTAP) in hearing: gene
disruption by chromosomal rearrangement in a hearing impaired individual
and model organism analysis. Am. J. Med. Genet. 143A: 1630-1639,
2007.
*FIELD* CN
Cassandra L. Kniffin - updated: 5/3/2012
Marla J. F. O'Neill - updated: 12/6/2011
Patricia A. Hartz - updated: 11/2/2010
Marla J. F. O'Neill - updated: 5/30/2008
Alan F. Scott - updated: 9/25/1996
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 05/03/2012
terry: 5/3/2012
ckniffin: 5/3/2012
terry: 12/6/2011
mgross: 11/3/2010
terry: 11/2/2010
carol: 6/3/2008
terry: 5/30/2008
mgross: 4/8/1999
terry: 9/25/1996
mark: 9/25/1996
terry: 8/28/1996
terry: 7/16/1996
mark: 7/24/1995
carol: 6/6/1994
carol: 7/8/1992
supermim: 3/16/1992
carol: 6/11/1990
supermim: 3/20/1990