Alternative titles; symbols
HGNC Approved Gene Symbol: TYMP
Cytogenetic location: 22q13.33 Genomic coordinates (GRCh38): 22:50,525,752-50,530,085 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q13.33 | Mitochondrial DNA depletion syndrome 1 (MNGIE type) | 603041 | Autosomal recessive | 3 |
The TYMP gene encodes thymidine phosphorylase (EC 2.4.2.4), a cytosolic enzyme that catalyzes the phosphorylation of thymidine or deoxyuridine to thymine or uracil, and is thus essential for the nucleotide salvage pathway (review by Suomalainen and Isohanni, 2010). The protein product was originally identified as platelet-derived endothelial cell growth factor (PDECGF), an angiogenic factor distinct from the previously described endothelial cell mitogens of the fibroblast growth factor family (Ishikawa et al., 1989). PDECGF is stored in platelets as a 45-kD single polypeptide chain and has a highly restricted target cell specificity acting only on endothelial cells. It promotes angiogenesis in vivo, and stimulates the in vitro growth of a variety of endothelial cells.
Ishikawa et al. (1989) isolated clones corresponding to the PDECGF gene from a placenta cDNA library. The deduced 482-residue protein had a molecular mass of 49.97 kD; Northern blot analysis detected a 1.8-kb mRNA transcript. Expression studies showed that the clone had growth-promoting activity for porcine aortic endothelial cells and a chemotactic effect for bovine endothelial cells, as well as angiogenic activity in mouse tumors. The findings confirmed that PDECGF acts as a potent angiogenic factor and likely plays a role in the maintenance of blood vessels.
Usuki et al. (1992) found that the PDECGF protein shared 39.2% amino acid sequence similarity over a 439-amino acid region with thymidine phosphorylase in E. coli. They found that the enzyme occurs as a 90-kD homodimer, similar to other thymidine phosphorylases.
Asai et al. (1992) found that gliostatin, a homodimeric structure of two 50-kD subunits, was identical to PDECGF.
Matsukawa et al. (1996) found ubiquitous expression of the PDECGF gene in various human tissues and organs, with relatively high levels in the digestive system, including esophagus and rectum, as well as in brain, spleen, bladder and lung. There was little or no expression in gallbladder, aorta, muscle, fat, and kidney. In addition, most human tumor cell lines showed 4- or 5-fold higher expression of the protein than normal tissue.
Hagiwara et al. (1991) determined that the PDECGF gene contains 10 exons spanning more than 4.3 kb.
Using an ECGF1 cDNA probe, Stenman et al. (1991, 1992) assigned the ECGF1 gene to chromosome 22 by analysis of its segregation in a panel of human/rodent somatic cell hybrids. By in situ hybridization, they sublocalized the gene to 22q13. The ECGF1 gene is in the same region as the PDGFB gene (190040) but is located distal to the 22q13 breakpoint in hybrid 1/22AM27, while PDGFB is proximal to this breakpoint.
Usuki et al. (1992) demonstrated that PDECGF has thymidine phosphorylase activity.
Asai et al. (1992) found that gliostatin and PDECGF shared growth inhibition of glial cells and growth promotion of endothelial cells, suggesting that both factors evoke the biologic actions through an identical receptor on each cell surface. Asai et al. (1992) also demonstrated a novel neurotrophic action of gliostatin/PDECGF toward embryonic rat cortical neurons in culture. These data indicated that gliostatin/PDECGF may play important roles in development and regeneration of the central nervous system, and may also involve the induction of angiogenesis for the formation of blood-brain barrier.
Griffiths and Stratford (1997) reviewed the major functions of PDECGF. In addition to being chemotactic for endothelial cells in vitro and angiogenic in vivo, it promotes neuronal survival (gliostatin), and catalyzes the reversible phosphorylation of thymidine to thymine (thymidine phosphorylase). Thymidine phosphorylase activity is critical for angiogenic activity. The PDECGF protein is highly expressed in tumors compared with most normal tissues and has been correlated with tumor growth, invasion, and metastasis in clinical studies. In addition, thymidine phosphorylase activity has been found to be a major determinant of the toxicity of 5-fluorouracil and its prodrugs, which are used clinically as anticancer agents.
In 12 probands with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), which manifests as mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), Nishino et al. (1999) identified 10 homozygous or compound heterozygous mutations in the TYMP gene (see, e.g., 131222.0001-131222.0008). TYMP activity in leukocytes from these patients was less than 5% of controls, indicating that loss-of-function mutations in TYMP cause the disorder. Studies of skeletal muscle showed multiple mitochondrial DNA deletions in 7 of 9 patients tested. Nishino et al. (1999) noted that TYMP is expressed at only low levels in skeletal muscle, suggesting that these mtDNA deletions may be an epiphenomenon. The authors hypothesized that aberrant thymidine metabolism leads to impaired replication or maintenance of mtDNA, causing mtDNA depletion, deletion, or both.
In a patient with a classic MNGIE clinical presentation but without skeletal muscle involvement at the morphologic, enzymatic, or mtDNA level, Szigeti et al. (2004) identified a homozygous splice site mutation in the TYMP gene (131222.0010). Szigeti et al. (2004) concluded that it is important to examine the most significantly affected tissue and to measure thymidine phosphorylase activity and plasma thymidine to arrive at an accurate diagnosis in this condition.
Hirano et al. (2005) demonstrated that TYMP activity was decreased to about 1.5% of control values in leukocytes derived from patients with MNGIE due to TYMP mutations. Asymptomatic heterozygous mutation carriers had about 35% residual TYMP activity.
Marti et al. (2005) reported 3 unrelated patients with late-onset MNGIE confirmed by the identification of TYMP mutations (131222.0011-131222.0014). The patients developed symptoms at ages 40 to 52 years, later than that observed in patients with typical MNGIE. Plasma deoxythymidine levels were mildly elevated, ranging from 0.4 to 1.4 microM, indicating that even low levels are pathogenic. Biochemical analysis showed 9 to 16% residual TYMP activity, which likely accounted for the later onset in these patients. Unaffected heterozygous mutation carriers had 26 to 35% residual TYMP activity, suggesting a minimal level required to prevent disease.
Murine uridine phosphorylate, unlike human UPP1 (191730), cleaves thymidine as well as uridine. To knock out Tymp activity in mice, Haraguchi et al. (2002) created Upp1/Tymp double-knockout mice. They found no alterations in mitochondrial DNA or pathologic changes in the muscles of double-knockout mice, even when these mice were fed thymidine for 7 months. However, they found intense lesions in the brain on T2-weighted MRI, and axonal edema by electron microscopic study of the brain of double-knockout mice. Haraguchi et al. (2002) concluded that inhibition of TYMP activity causes elevation of pyrimidine levels in plasma and consequent axonal swelling.
Replication and repair of DNA require equilibrated pools of deoxynucleoside triphosphate precursors. Lopez et al. (2009) generated Tymp and Upp1 double-knockout mice, which showed severe Tymp deficiency, increased thymidine and deoxyuridine in tissues, and elevated mitochondrial deoxythymidine triphosphate. As consequences of the nucleotide pool imbalances, brains of mutant mice developed partial depletion of mtDNA, deficiencies of respiratory chain complexes, and encephalopathy. These findings largely account for the pathogenesis of MNGIE, the first inherited human disorder of nucleoside metabolism associated with somatic DNA instability.
In patients with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Nishino et al. (1999) identified a 3371A-C transversion in exon 7 of the ECGF1 gene, resulting in a glu289-to-ala (E289A) substitution. This mutation was seen in homozygosity in an Ashkenazi Jewish patient and in compound heterozygosity in 4 other patients of German American (131222.0002), German (131222.0006), English (131222.0008), and European American ancestry. The mutation was associated with mitochondrial deletions in skeletal muscle, presumably resulting from mtDNA depletion.
In a patient with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Nishino et al. (1999) identified compound heterozygosity for 2 mutations in the TYMP gene: E289A (131222.0001), and a 1504T-C transition in intron 4 that altered the splice donor site. When assayed by RT-PCR in leukocytes, the latter mutation caused skipping of exon 4. This would lead to loss of 33 amino acids in the mature protein and deletion of the thymidine phosphorylase consensus. The mutations were associated with mitochondrial deletions in skeletal muscle, presumably resulting from mtDNA depletion.
In patients with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Nishino et al. (1999) identified a 1419A-C transversion in exon 4 of the ECGF1 gene, causing a gly145-to-arg (G145R) substitution. The mutation was found in homozygosity in 2 Puerto Rican and 1 Israeli patient. The mutation, in the region of the thymidine phosphorylase consensus, was associated with multiple mtDNA deletions in skeletal muscle, presumably resulting from mtDNA depletion.
Nishino et al. (2000) reported an African American patient with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), who was compound heterozygous for 2 mutations in the TYMP gene: a 2744A-G transition, resulting in a lys222-to-arg (L222R) substitution, and a 1-bp insertion (4196insC; 131222.0005). This patient had previously been described by Nishino et al. (1999), who found that the missense mutation disrupted the thymidine phosphorylase phosphate binding site and that the mutations were associated with multiple mtDNA deletions in skeletal muscle, presumably resulting from mtDNA depletion. (Nishino et al. (1999) erroneously stated that the missense mutation in this patient, who was described as Jamaican, was a lys222-to-ser (K222S) substitution.)
For discussion of the 1-bp insertion in the TYMP gene (4196insC) that was found in compound heterozygous state in a patient with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) by Nishino et al. (2000) and Nishino et al. (1999), see 131222.0004.
In a patient with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Nishino et al. (1999) identified compound heterozygosity for 2 mutations in the TYMP gene: E289A (131222.0001), and a 3867G-C transversion that disrupted the splice acceptor site of intron 8, leading to skipping of exon 9 and disruption of the leucine zipper motif.
In a patient with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Nishino et al. (1999) identified a homozygous 6-bp deletion in exon 9 of the ECGF1 gene that resulted in loss of leucine-397 and alanine-398. Although neither amino acid is strictly conserved, the authors suggested that their loss could alter the structure and enzymatic activity of the thymidine phosphorylase protein.
In patients with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Nishino et al. (1999) identified a 1443G-A transition in the ECGF1 gene, resulting in a gly153-to-ser (G153S) substitution. The mutation was identified in homozygosity in an English patient and in compound heterozygosity with the E289A mutation (131222.0001) in another English and 1 European American patient.
In 2 Spanish sisters with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Gamez et al. (2002) identified a homozygous 435G-A transition in the ECGF1 gene, resulting in an arg44-to-gln (R44Q) substitution in the mature protein. The authors noted that arg44 is located in the N-terminal domain of the protein and that the substitution of a positively charged (arg) by an uncharged (gln) amino acid could account for loss of enzyme activity in the 2 affected sisters. The mother and an unaffected sister were heterozygous for the mutation. Clinically, the affected sisters presented with variable phenotypes: one had predominantly gastrointestinal symptoms and the other had ophthalmoparesis.
In a patient with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as classic mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) but without skeletal muscle involvement at the morphologic, enzymatic, or mtDNA level, Szigeti et al. (2004) identified a homozygous G-to-C transversion at the splice acceptor site of exon 2 of the ECGF1 gene. The mutation resulted in skipping of exon 2 and loss of function of the protein, which was confirmed by the markedly reduced enzyme activity measured in peripheral blood.
In 2 unrelated women with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as late-onset mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Marti et al. (2005) identified compound heterozygosity for 2 mutations in the ECGF1 gene. Both patients had a 2398G-A transition, resulting in a val208-to-met (V208M) substitution. In addition, 1 patient had a 3535G-C transversion, resulting in a gly311-to-arg substitution (G311R; 131222.0012), and the other had a 2381G-C transversion, resulting in an arg202-to-thr substitution (R202T; 131222.0013). The patients had onset of gastrointestinal symptoms at age 42 and 40 years, respectively. Biochemical analysis showed 15 to 16% residual enzyme activity in both patients, which likely accounted for the later onset.
For discussion of the gly311-to-arg (G311R) mutation in the TYMP gene that was found in compound heterozygous state in patients with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as late-onset mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), by Marti et al. (2005), see 131222.0011.
For discussion of the arg202-to-thr (R202T) mutation in the TYMP gene that was found in compound heterozygous state in patients with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as late-onset mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), by Marti et al. (2005), see 131222.0011.
In an African American man with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041) manifest as late-onset mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Marti et al. (2005) identified compound heterozygosity for 2 mutations in the ECGF1 gene: a 3359T-C transition, resulting in a leu285-to-pro (L285P) substitution, and a G153S mutation (131222.0008). The patient had onset of lower gastrointestinal bleeding at age 52 years, followed by peripheral neuropathy, external ophthalmoplegia, and leukoencephalopathy. Biochemical analysis showed 9 to 13% residual enzyme activity, which likely accounted for the later onset.
Asai, K., Nakanishi, K., Isobe, I., Eksioglu, Y. Z., Hirano, A., Hama, K., Miyamoto, T., Kato, T. Neurotrophic action of gliostatin on cortical neurons: identity of gliostatin and platelet-derived endothelial cell growth factor. J. Biol. Chem. 267: 20311-20316, 1992. [PubMed: 1400349]
Gamez, J., Ferreiro, C., Accarino, M. L., Guarner, L., Tadesse, S., Marti, R. A., Andreu, A. L., Raguer, N., Cervera, C., Hirano, M. Phenotypic variability in a Spanish family with MNGIE. Neurology 59: 455-457, 2002. [PubMed: 12177387] [Full Text: https://doi.org/10.1212/wnl.59.3.455]
Griffiths, L., Stratford, I. J. Platelet-derived endothelial cell growth factor thymidine phosphorylase in tumour growth and response to therapy. Brit. J. Cancer 76: 689-693, 1997. [PubMed: 9310231] [Full Text: https://doi.org/10.1038/bjc.1997.447]
Hagiwara, K., Stenman, G., Honda, H., Sahlin, P., Andersson, A., Miyazono, K., Heldin, C. H., Ishikawa, F., Takaku, F. Organization and chromosomal localization of the human platelet-derived endothelial cell growth factor gene. Molec. Cell. Biol. 11: 2125-2132, 1991. [PubMed: 2005900] [Full Text: https://doi.org/10.1128/mcb.11.4.2125-2132.1991]
Haraguchi, M., Tsujimoto, H., Fukushima, M., Higuchi, I., Kuribayashi, H., Utsumi, H., Nakayama, A., Hashizume, Y., Hirato, J., Yoshida, H., Hara, H., Hamano, S., and 17 others. Targeted deletion of both thymidine phosphorylase and uridine phosphorylase and consequent disorders in mice. Molec. Cell. Biol. 22: 5212-5221, 2002. [PubMed: 12077348] [Full Text: https://doi.org/10.1128/MCB.22.14.5212-5221.2002]
Hirano, M., Lagier-Tourenne, C., Valentino, M. L., Marti, R., Nishigaki, Y. Thymidine phosphorylase mutations cause instability of mitochondrial DNA. Gene 354: 152-156, 2005. [PubMed: 15975738] [Full Text: https://doi.org/10.1016/j.gene.2005.04.041]
Ishikawa, F., Miyazono, K., Hellman, U., Drexler, H., Wernstedt, C., Hagiwara, K., Usuki, K., Takaku, F., Risau, W., Heldin, C.-H. Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor. Nature 338: 557-562, 1989. [PubMed: 2467210] [Full Text: https://doi.org/10.1038/338557a0]
Lopez, L. C., Akman, H. O., Garcia-Cazorla, A., Dorado, B., Marti, R., Nishino, I., Tadesse, S., Pizzorno, G., Shungu, D., Bonilla, E., Tanji, K., Hirano, M. Unbalanced deoxynucleotide pools cause mitochondrial DNA instability in thymidine phosphorylase-deficient mice. Hum. Molec. Genet. 18: 714-722, 2009. [PubMed: 19028666] [Full Text: https://doi.org/10.1093/hmg/ddn401]
Marti, R., Verschuuren, J. J. G. M., Buchman, A., Hirano, I., Tadesse, S., van Kuilenburg, A. B. P., van Gennip, A. H., Poorthuis, B. J. H. M., Hirano, M. Late-onset MNGIE due to partial loss of thymidine phosphorylase activity. Ann. Neurol. 58: 649-652, 2005. [PubMed: 16178026] [Full Text: https://doi.org/10.1002/ana.20615]
Matsukawa, K., Moriyama, A., Kawai, Y., Asai, K., Kato, T. Tissue distribution of human gliostatin/platelet-derived endothelial cell growth factor (PD-ECGF) and its drug-induced expression. Biochim. Biophys. Acta 1314: 71-82, 1996. [PubMed: 8972720] [Full Text: https://doi.org/10.1016/s0167-4889(96)00078-x]
Nishino, I., Spinazzola, A., Hirano, M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 283: 689-692, 1999. [PubMed: 9924029] [Full Text: https://doi.org/10.1126/science.283.5402.689]
Nishino, I., Spinazzola, A., Papadimitriou, A., Hammans, S., Steiner, I., Hahn, C. D., Connolly, A. M., Verloes, A., Guimaraes, J., Maillard, I., Hamano, H., Donati, M. A., and 13 others. Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations. Ann. Neurol. 47: 792-800, 2000. [PubMed: 10852545]
Stenman, G., Sahlin, P., Dumanski, J. P., Hagiwara, K., Ishikawa, F., Miyazono, K., Collins, V. P., Heldin, C.-H. Regional localization of the human platelet-derived endothelial cell growth factor (ECGF1) gene to chromosome 22q13. Cytogenet. Cell Genet. 59: 22-23, 1992. [PubMed: 1733667] [Full Text: https://doi.org/10.1159/000133191]
Stenman, G., Sahlin, P., Hagiwara, K., Dumanski, J., Collins, V., Heldin, C.-H. Mapping of the human platelet-derived endothelial cell growth factor (PD-ECGF) gene to chromosome 22q13. (Abstract) Cytogenet. Cell Genet. 58: 2051 only, 1991.
Suomalainen, A., Isohanni, P. Mitochondrial DNA depletion syndromes: many genes, common mechanisms. Neuromusc. Disord. 20: 429-437, 2010. [PubMed: 20444604] [Full Text: https://doi.org/10.1016/j.nmd.2010.03.017]
Szigeti, K., Wong, L.-J. C., Perng, C.-L., Saifi, G. M., Eldin, K., Adesina, A. M., Cass, D. L., Hirano, M., Lupski, J. R., Scaglia, F. MNGIE with lack of skeletal muscle involvement and a novel TP splice site mutation. J. Med. Genet. 41: 125-129, 2004. [PubMed: 14757860] [Full Text: https://doi.org/10.1136/jmg.2003.013789]
Usuki, K., Saras, J., Waltenberger, J., Miyazono, K., Pierce, G., Thomason, A., Heldin, C.-H. Platelet-derived endothelial cell growth factor has thymidine phosphorylase activity. Biochem. Biophys. Res. Commun. 184: 1311-1316, 1992. [PubMed: 1590793] [Full Text: https://doi.org/10.1016/s0006-291x(05)80025-7]