Alternative titles; symbols
HGNC Approved Gene Symbol: MAT2A
Cytogenetic location: 2p11.2 Genomic coordinates (GRCh38): 2:85,539,168-85,545,281 (from NCBI)
The MAT2A gene encodes the catalytic subunit of extrahepatic methionine adenosyltransferase (EC 2.5.1.6) (MAT II), which catalyzes the biosynthesis of S-adenosylmethionine (AdoMet, or SAM) from methionine and ATP (summary by Mao et al., 1998).
AdoMet is the major methyl donor for many of the transmethylation reactions in the body. Chamberlin et al. (1996) noted that AdoMet also participates in the transsulfuration pathway and, after decarboxylation, serves as a propylamine group donor in the biosynthesis of polyamines. Three forms of MAT have been identified in mammalian tissues. MAT I and MAT III, which are encoded by the single-copy MAT1A gene (610550), represent tetramers and dimers, respectively, formed from identical alpha-1 subunits and are synthesized primarily in the liver. MAT II, encoded by a separate gene, which was cloned by Horikawa and Tsukada (1992), is found in fetal liver (and to a lesser extent in adult liver) as well as in kidney, brain, testis, and lymphocytes. Horikawa and Tsukada (1992) showed that the 395-amino acid MAT II shares 84% amino acid similarity with the human liver MAT I/III protein.
Mao et al. (1998) cloned the 5-prime flanking region of the MAT2A gene. They identified 2 major transcriptional start sites, one located within 10 nucleotides downstream and the other 158 nucleotides upstream from the TATA box. The MAT2A promoter is highly GC rich, especially in the first 300 bp. The promoter contains several potential SP1-, v-myb-, and GATA-binding sites, as well as potential binding sites for C/EBP, HSF2, c-myb, and STATx. Mao et al. (1998) showed that the MAT2A promoter can efficiently drive expression from a reporter gene in both Jurkat and 293 cells. The authors identified regions of the promoter that are important for cell-specific MAT2A expression.
O'Leary et al. (2015) determined that the MAT2A gene contains 9 exons. Its promoter region contains a CpG island that partly overlaps the PARTICLE gene on the opposite strand.
By in situ hybridization, De La Rosa et al. (1995) mapped the MATA2 gene to chromosome 2p11.2.
Using Northern blot analysis and in situ hybridization, O'Leary et al. (2015) found that low-dose (0.25 Gy) gamma irradiation of several human cell lines led to an early increase in expression of MAT2A, followed by increased expression of the long noncoding RNA PARTICLE (PARTICL; 616350). Low-dose irradiation of human breast cancer cells also led to secretion of MAT2A, PARTICLE, and SAM into the culture medium. Higher doses of radiation (2.50 Gy) had a weaker effect in all assays. In vitro irradiation of whole normal donor blood, as well as radiation therapy in head and neck cancer patients, caused a similar increase in circulating PARTICLE and MAT2A RNA. Knockdown of PARTICLE via short hairpin RNA enhanced expression of MAT2A mRNA and protein, increased MAT2A reporter gene activity, and increased intracellular and extracellular SAM concentration following low-dose irradiation. O'Leary et al. (2015) determined that the PARTICLE gene partly overlaps a CpG island in the promoter region of the MAT2A gene. Low-dose irradiation induced methylation of this CpG island, and this methylation was abrogated by knockdown of PARTICLE. PARTICLE formed an RNA-DNA triple helix with the promoter region of the MAT2A gene 456 bp upstream of the CpG island. Chromatin immunoprecipitation analysis and EMSA showed that PARTICLE interacted with gene-silencing factors, including the lysine methyltransferase G9A (EHMT2; 604599) and the transcription factor MYB (189990), and that it interacted directly with the polycomb repressor complex (PRC) subunit SUZ12 (606245). O'Leary et al. (2015) concluded that PARTICLE recruits G9A, MYB, and SUZ12 to the MAT2A promoter for gene silencing.
For discussion of a possible association between variation in the MAT2A gene and thoracic aortic aneurysm, see 601468.0001.
Guo et al. (2015) examined mat2aa -/- zebrafish at 72 days postfertilization (dpf) and observed moderately affected morphants with a large pericardial effusion and small eyes, as well as severely affected morphants that also exhibited a curly tail or severe tail curvature. All morphants showed significant defects in the development of the aortic arches at 3 dpf. Coinjection of either wildtype or mutant MAT2A mRNA partially rescued the morphant phenotypes, but wildtype MAT2A rescued the developmental defects at a significantly higher frequency than the E344A (601468.0001) or R356H mutants.
This variant is classified as a variant of unknown significance because its contribution to thoracic aortic aneurysm (AAT; see 607086) has not been confirmed.
In 2 affected individuals from a large 3-generation family (family TAA059) segregating autosomal dominant thoracic aortic aneurysm with reduced penetrance and negative for mutation in known AAT-associated genes, Guo et al. (2015) performed exome sequencing and identified heterozygosity for a c.1031A-C transversion (c.1031A-C, NM_005911.5) in the MAT2A gene, resulting in a glu344-to-ala (E344A) substitution at a highly conserved residue. The mutation, which was not present in public variant databases, was detected in 18 family members, all of whom underwent evaluation for thoracic aorta disease and bicuspid aortic valve. Eight (44%) of the mutation-positive individuals were diagnosed with dilation of the ascending aorta and/or aortic root at a median age of 50 years, including 3 who also exhibited bicuspid aortic valve; 10 (56%) of the mutation carriers, with a median age of 30 years, did not have aortic disease, although 1 had bicuspid aortic valve. None of the mutation carriers had other cardiac disease, and no systemic features of Marfan or Loeys-Dietz syndrome were found in 4 patients who were evaluated by a geneticist. Aortic tissue excised during aneurysm repair in 2 patients showed mild medial degeneration characterized by focal areas of increased proteoglycan deposition and fragmentation of elastic fibers but minimal loss of smooth muscle cells. Analysis of an additional 525 probands with AAT revealed 1 with a different missense mutation in the MAT2A gene (R356H), but that proband also carried a missense mutation in a known AAT-associated gene, ACTA2 (102620). Guo et al. (2015) concluded that MAT2A mutations predispose individuals to thoracic aortic disease and suggested that a second 'hit' might be required.
Chamberlin, M. E., Ubagai, T., Mudd, S. H., Wilson, W. G., Leonard, J. V., Chou, J. Y. Demyelination of the brain is associated with methionine adenosyltransferase I/III deficiency. J. Clin. Invest. 98: 1021-1027, 1996. [PubMed: 8770875] [Full Text: https://doi.org/10.1172/JCI118862]
De La Rosa, J., Ostrowski, J., Hryniewicz, M. M., Kredich, N. M., Kotb, M., LeGros, H. L., Jr., Valentine, M., Geller, A. M. Chromosomal localization and catalytic properties of the recombinant alpha subunit of human lymphocyte methionine adenosyltransferase. J. Biol. Chem. 270: 21860-21868, 1995. [PubMed: 7665609] [Full Text: https://doi.org/10.1074/jbc.270.37.21860]
Guo, D., Gong, L., Regalado, E. S., Santos-Cortez, R. L., Zhao, R., Cai, B., Veeraraghavan, S., Prakash, S. K., Johnson, R. J., Muilenburg, A., Willing, M., Jondeau, G., and 14 others. MAT2A mutations predispose individuals to thoracic aortic aneurysms. Am. J. Hum. Genet. 96: 170-177, 2015. [PubMed: 25557781] [Full Text: https://doi.org/10.1016/j.ajhg.2014.11.015]
Horikawa, S., Tsukada, K. Molecular cloning and developmental expression of a human kidney S-adenosylmethionine synthetase. FEBS Lett. 312: 37-41, 1992. [PubMed: 1426236] [Full Text: https://doi.org/10.1016/0014-5793(92)81405-b]
Mao, Z., Liu, S., Cai, J., Huang, Z.-Z., Lu, S. C. Cloning and functional characterization of the 5-prime-flanking region of human methionine adenosyltransferase 2A gene. Biochem. Biophys. Res. Commun. 248: 479-484, 1998. [PubMed: 9703951] [Full Text: https://doi.org/10.1006/bbrc.1998.8965]
O'Leary, V. B., Ovsepian, S. V., Carrascosa, L. G., Buske, F. A., Radulovic, V., Niyazi, M., Moertl, S., Trau, M., Atkinson, M. J., Anastasov, N. PARTICLE, a triplex-forming long ncRNA, regulates locus-specific methylation in response to low-dose irradiation. Cell Rep. 11: 474-485, 2015. [PubMed: 25900080] [Full Text: https://doi.org/10.1016/j.celrep.2015.03.043]