Alternative titles; symbols
HGNC Approved Gene Symbol: MTAP
Cytogenetic location: 9p21.3 Genomic coordinates (GRCh38): 9:21,802,636-21,941,115 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p21.3 | Diaphyseal medullary stenosis with malignant fibrous histiocytoma | 112250 | Autosomal dominant | 3 |
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).
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.
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.
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.
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.
The MTAP gene is frequently deleted in human cancers because of its chromosomal proximity to the tumor suppressor gene CDKN2A. By interrogating data from a large-scale short hairpin RNA-mediated screen across 390 cancer cell line models, Mavrakis et al. (2016) found that the viability of MTAP-deficient cancer cells is impaired by depletion of the protein arginine methyltransferase PRMT5 (604045). MTAP-deleted cells accumulate the metabolite methylthioadenosine (MTA), which the authors found inhibited PRMT5 methyltransferase activity. Deletion of MTAP in MTAP-proficient cells rendered them sensitive to PRMT5 depletion. Conversely, reconstitution of MTAP in an MTAP-deficient cell line rescued PRMT5 dependence. Thus, MTA accumulation in MTAP-deleted cancers creates a hypomorphic PRMT5 state that is selectively sensitized toward further PRMT5 inhibition.
Kryukov et al. (2016) discovered that loss of the enzyme MTAP confers a selective dependence on PRMT5 and its binding partner WDR77 (611734). Kryukov et al. (2016) also observed increased intracellular concentrations of MTA, the metabolite cleaved by MTAP, in cells harboring MTAP deletions. Furthermore, MTA specifically inhibited PRMT5 enzymatic activity. Administration of either MTA or a small-molecule PRMT5 inhibitor showed a modest preferential impairment of cell viability for MTAP-null cancer cell lines compared with isogenic MTAP-expressing counterparts. Together, their findings revealed PRMT5 as a potential vulnerability across multiple cancer lineages augmented by a common 'passenger' genomic alteration.
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.
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.
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.
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.
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.
Arnold, W. H. Hereditary bone dysplasia with sarcomatous degeneration. Ann. Intern. Med. 78: 902-906, 1973. [PubMed: 4713573] [Full Text: https://doi.org/10.7326/0003-4819-78-6-902]
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. [PubMed: 21532571] [Full Text: https://doi.org/10.1038/ng.824]
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. [PubMed: 22464254] [Full Text: https://doi.org/10.1016/j.ajhg.2012.02.024]
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. [PubMed: 6425836] [Full Text: https://doi.org/10.1073/pnas.81.9.2665]
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. [PubMed: 3925340] [Full Text: https://doi.org/10.1056/NEJM198508013130503]
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. [PubMed: 3745248]
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. [PubMed: 13511301]
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. [PubMed: 19567676] [Full Text: https://doi.org/10.1158/0008-5472.CAN-09-0145]
Kryukov, G. V., Wilson, F. H., Ruth, J. R., Paulk, J., Tsherniak, A., Marlow, S. E., Vazquez, F., Weir, B. A., Fitzgerald, M. E., Tanaka, M., Bielski, C. M., Scott, J. M., and 9 others. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science 351: 1214-1218, 2016. [PubMed: 26912360] [Full Text: https://doi.org/10.1126/science.aad5214]
Mavrakis, K. J., McDonald, E. R., III, Schlabach, M. R., Billy, E., Hoffman, G. R., deWeck, A., Ruddy, D. A., Venkatesan, K., Yu, J., McAllister, G., Stump, M., deBeaumont, R., and 32 others. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science 351: 1208-1213, 2016. [PubMed: 26912361] [Full Text: https://doi.org/10.1126/science.aad5944]
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. [PubMed: 16419137] [Full Text: https://doi.org/10.1002/ajmg.a.31008]
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. [PubMed: 8650244] [Full Text: https://doi.org/10.1073/pnas.93.12.6203]
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. [PubMed: 8781110] [Full Text: https://doi.org/10.1007/BF01356833]
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. [PubMed: 1568221]
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. [PubMed: 7604019] [Full Text: https://doi.org/10.1073/pnas.92.14.6489]
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. [PubMed: 8687427] [Full Text: https://doi.org/10.1006/bbrc.1996.0926]
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. [PubMed: 16244874] [Full Text: https://doi.org/10.1007/s00439-005-0075-z]
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. [PubMed: 6803807] [Full Text: https://doi.org/10.1016/0006-2952(82)90171-x]
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. [PubMed: 17534888] [Full Text: https://doi.org/10.1002/ajmg.a.31724]