MTAP

Gene Facts

• HGNC Symbol: MTAP (HGNC:7413)
• HGNC Name: methylthioadenosine phosphorylase
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: MSAP, c86fus
• %HI: 38.31
• pLI: 0
• LOEUF: 1.49
• Cytoband: 9p21.3
• Genomic Coordinates:

  GRCh37/hg19:	chr9:21802635-21867080
  GRCh38/hg38:	chr9:21802636-21941115

• MANE Select Transcript: NM_002451.4 ENST00000644715.2
• Function: Catalyzes the reversible phosphorylation of S-methyl-5'- thioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. Involved in the breakdown of MTA, a major by-product of polyamine biosynthesis. Responsible for the first step in the methionine salvage pathway after MTA has been generated from S-adenosylmethionine. Has broad substrate specificity with 6-aminopurine nucleosides as preferred substrates. {ECO:0000255|HAMAP-Rule:MF_03155, ECO:0000269|PubMed:3091600}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-3408
• ClinGen Curation ID: CCID:007490
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Little Evidence for Haploinsufficiency (1)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 10/12/2022

Haploinsufficiency (HI) Score Details

• HI Score: 1
• HI Evidence Strength: Little Evidence for Haploinsufficiency
• HI Evidence Comments: Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) has been described as an autosomal-dominant syndrome characterized by bone dysplasia, myopathy, and bone cancer [MIM 112250]. Camacho-Vanegas et al. first reported that DMS-MFH resulted from variants in the MTAP gene encoding methylthioadenosine (MTA) phosphorylase [PMID:22464254], though previous studies have described this condition and mapped the DMS-MFH locus to chromosomal region 9p21–22 but have failed to identify mutations in known genes in this region [Norton 1996, PMID: 8781110; Martignetti 1999, PMID: 10053015]. The study carried out by Camacho-Vanegas et al. identified two different heterozygous variants involving the previously uncharacterized exon 9 of the MTAP gene in affected members of five unrelated families with DMSMFH. These variants were absent in non-affected family members tested, indicating the two variants segregated with the disease in these families. RNA analysis showed that the two reported variants, one synonymous and one splice variant, impacted splicing, resulting in multiple isoforms in addition to the archetype MTAP transcript. None of the six additional isoforms contained the WT terminal exon 8, and all affected the C terminus of the protein product in different ways. The expression of MTAP exon-9 containing isoforms was reduced, but the expression level of two transcripts without exon 9 was markedly elevated in both mutant constructs. Serum samples from two patients showed accumulation of MTA, whereas MTA was not present in serum from the three controls. These findings implicated patients with MTAP mutations had a defect in MTAP enzyme activity. DNA analysis of tumor tissue from osteosarcomas revealed frequent loss or loss of heterozygosity (LOH) of the wildtype allele, leading to homozygosity for the MTAP mutation in the tumor [Garcia-Castellano 2002, PMID: 11895909]. The findings of the study imply that MTAP acts as a tumor suppressor gene. While heterozygous knockout of MTAP in mice does not cause osteosarcoma, these mice display T-cell lymphoma and the homozygous knockout is embryonic lethal, which indicates the essential nature of the MTAP gene [Williamson 2007, PMID: 17534888; Kadariya 2009, PMID: 19567676]. In addition, the reintroduction of MTAP expression into the MCF7 breast adenocarcinoma cell line, which lacks endogenous MTAP gene expression and enzymatic activity, inhibits the cells’ ability to grow both in vitro and in vivo; the fact that MTAP inhibits cell growth is consistent with its presumed role as a tumor suppressor [Christopher 2002, PMID: 12438261]. The ClinGen group determined there was moderate evidence to support the relationship between MTAP and DMSMFH on 6/15/2021. However, the evidence to support haploinsufficiency is still conflicting and insufficient. The intriguing aspect of this study is the terminal MTAP exons after exon 8. Although the transcript (ENSG00000099810.18) in gtex (https://gtexportal.org/home/gene/MTAP) shows the expression level of all 12 exons, none of the transcripts listed in UCSC (Hg19 and hg38) and gnomAD contain all 12 exons. The default transcript (NM_002451) in HGMD contains 8 previously described exons, and variants in these exons of MTAP, including several missense variants and one nonsense variant in exon 6, have been reported in patients with developmental disorders, different malignancies, and hearing loss. The transcript linked to DMS-MFH was not available in HGMD. Loss of function (LOF) variants in these exons are also frequent in gnomAD, suggesting this gene tolerates the LOF alterations, though this could be related to incomplete disease penetrance. In addition, the loss or LOH of WT MTAP observed in osteosarcomas could be complicated by the location of MTAP, which lies within 25 kb of the CDKN2A/B genes. Whole or partial chromosome 9p, including CDKN2A/B, is frequently lost or shows LOH in human cancers, and these changes can extend to the MTAP gene, which was reported to result in biallelic loss of MTAP in the osteosarcoma observed. Finally, the overexpression of the two splice isoforms (lack of exon 9) derived from the patients may indicate their oncogenic effects on tumorigenesis. Given that changes in MTAP have been associated with this phenotype but the disease mechanism of MAP7-related disorders is still unclear and LOF variants are commonly observed in general populations, we are giving this gene a haploinsufficiency score of 1, to reflect the "emerging" evidence surrounding this gene. Additional information will be necessary to confirm this association, elucidate the full phenotypic and variant spectrum, and determine whether or not haploinsufficiency truly plays a role in the development of this phenotype.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity