mitochondrial C1 tetrahydrofolate synthase


Gene Symbol: mitochondrial C1 tetrahydrofolate synthase
Description: methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1 like
Alias: FTHFSDC1, MTC1THFS, dJ292B18.2, monofunctional C1-tetrahydrofolate synthase, mitochondrial, 10-formyl-THF synthetase, formyltetrahydrofolate synthetase domain containing 1
Species: human

Top Publications

  1. Sugiura T, Nagano Y, Inoue T, Hirotani K. A novel mitochondrial C1-tetrahydrofolate synthetase is upregulated in human colon adenocarcinoma. Biochem Biophys Res Commun. 2004;315:204-11 pubmed
    ..These results suggest that mtC(1)-THFS may participate in the progression of colorectal cancer by conferring growth advantage and could be a new molecular target for cancer therapy. ..
  2. Prasannan P, Pike S, Peng K, Shane B, Appling D. Human mitochondrial C1-tetrahydrofolate synthase: gene structure, tissue distribution of the mRNA, and immunolocalization in Chinese hamster ovary calls. J Biol Chem. 2003;278:43178-43187 pubmed publisher
    ..Yeast cells expressing the full-length human cDNA exhibited elevated 10-formyl-THF synthetase activity, confirming its identification as the human mitochondrial C1-THF synthase. ..
  3. Naj A, Beecham G, Martin E, Gallins P, Powell E, Konidari I, et al. Dementia revealed: novel chromosome 6 locus for late-onset Alzheimer disease provides genetic evidence for folate-pathway abnormalities. PLoS Genet. 2010;6:e1001130 pubmed publisher
    ..This finding is noteworthy, as MTHFD1L may play a role in the generation of methionine from homocysteine and influence homocysteine-related pathways and as levels of homocysteine are a significant risk factor for LOAD development. ..
  4. Bressler J, Folsom A, Couper D, Volcik K, Boerwinkle E. Genetic variants identified in a European genome-wide association study that were found to predict incident coronary heart disease in the atherosclerosis risk in communities study. Am J Epidemiol. 2010;171:14-23 pubmed publisher
    ..This study demonstrates that genetic variants revealed in a case-control genome-wide association study enriched for early disease onset may play a role in the genetic etiology of CHD in the general population. ..
  5. Samani N, Erdmann J, Hall A, Hengstenberg C, Mangino M, Mayer B, et al. Genomewide association analysis of coronary artery disease. N Engl J Med. 2007;357:443-53 pubmed
    ..3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease. ..
  6. Parle McDermott A, Pangilinan F, O Brien K, Mills J, Magee A, Troendle J, et al. A common variant in MTHFD1L is associated with neural tube defects and mRNA splicing efficiency. Hum Mutat. 2009;30:1650-6 pubmed publisher
    ..We demonstrate that two of the three alleles of rs3832406 are functionally different and influence the splicing efficiency of the alternate MTHFD1L mRNA transcripts. ..
  7. Bidkhori G, Benfeitas R, Klevstig M, Zhang C, Nielsen J, Uhlen M, et al. Metabolic network-based stratification of hepatocellular carcinoma reveals three distinct tumor subtypes. Proc Natl Acad Sci U S A. 2018;115:E11874-E11883 pubmed publisher
  8. Taflin H, Odin E, Derwinger K, Carlsson G, Gustavsson B, Wettergren Y. Relationship between folate concentration and expression of folate-associated genes in tissue and plasma after intraoperative administration of leucovorin in patients with colorectal cancer. Cancer Chemother Pharmacol. 2018;82:987-997 pubmed publisher
    ..Expression of several folate-associated genes is associated with folate concentration in tissue and plasma and may become useful when predicting response to LV treatment. ..
  9. Jeemon P, Pettigrew K, Sainsbury C, Prabhakaran D, Padmanabhan S. Implications of discoveries from genome-wide association studies in current cardiovascular practice. World J Cardiol. 2011;3:230-47 pubmed publisher
    ..The future application of genetic screening will be in identifying risk groups early in life to direct targeted preventive measures. ..

More Information


  1. Bryant J, Sweeney S, Sentandreu E, Shin M, Ipas H, Xhemalce B, et al. Deletion of the neural tube defect-associated gene Mthfd1l disrupts one-carbon and central energy metabolism in mouse embryos. J Biol Chem. 2018;293:5821-5833 pubmed publisher
    ..These results indicate that disruptions of mitochondrial 1C metabolism have wide-ranging consequences for many metabolic processes, including those that may not directly interact with 1C metabolism. ..
  2. Xie Z, Yang X, Deng X, Ma M, Shu K. A Genome-Wide Association Study and Complex Network Identify Four Core Hub Genes in Bipolar Disorder. Int J Mol Sci. 2017;18: pubmed publisher
    ..Our method engenders new thoughts on finding genes indirectly associated with, but important for, complex diseases. ..
  3. Mazul A, Siega Riz A, Weinberg C, Engel S, Zou F, Carrier K, et al. A family-based study of gene variants and maternal folate and choline in neuroblastoma: a report from the Children's Oncology Group. Cancer Causes Control. 2016;27:1209-18 pubmed publisher
    ..Choline-related variants may play a role; however, the functional consequences of the interacting variants are unknown and require independent replication. ..
  4. Sudiwala S, de Castro S, Leung K, Brosnan J, Brosnan M, Mills K, et al. Formate supplementation enhances folate-dependent nucleotide biosynthesis and prevents spina bifida in a mouse model of folic acid-resistant neural tube defects. Biochimie. 2016;126:63-70 pubmed publisher
    ..We hypothesise that reduced Mthfd1L expression may contribute to susceptibility to NTDs in the curly tail strain and that formate acts as a one-carbon donor to prevent NTDs. ..
  5. Villalba M, Fredericksen F, Otth C, Olavarría V. Transcriptomic analysis of responses to cytopathic bovine viral diarrhea virus-1 (BVDV-1) infection in MDBK cells. Mol Immunol. 2016;71:192-202 pubmed publisher
    ..This meta-transcriptomic analysis provides the first data towards understanding the infection mechanisms of cytopathic BVDV-1 and the putative molecular relationship between viral and host components. ..
  6. Byström S, Fredolini C, Edqvist P, Nyaiesh E, Drobin K, Uhlen M, et al. Affinity Proteomics Exploration of Melanoma Identifies Proteins in Serum with Associations to T-Stage and Recurrence. Transl Oncol. 2017;10:385-395 pubmed publisher
    ..Our findings provide a starting point to further study RGN, STX7, MTHFD1L and S100A6 in serum to elucidate their involvement in melanoma progression and to assess a possible contribution to support clinical indications. ..
  7. Yang Y, Yuan Y, Hu W, Shang Q, Chen L. The role of mitochondrial folate enzyme MTHFD1L in esophageal squamous cell carcinoma. Scand J Gastroenterol. 2017;:1-8 pubmed publisher
    ..However, little information is available concerning the role of MTHFD1L in cancer cells, and no studies have addressed such issues in esophageal cancer...
  8. Minguzzi S, Molloy A, Peadar K, Mills J, Scott J, Troendle J, et al. Genotyping of a tri-allelic polymorphism by a novel melting curve assay in MTHFD1L: an association study of nonsyndromic Cleft in Ireland. BMC Med Genet. 2012;13:29 pubmed publisher
    ..Corrected p-values indicate no association between MTHFD1L and risk of cleft in an Irish cohort. ..
  9. Lee D, Wong C. The folate cycle is a new metabolic weakness of cancer. Mol Cell Oncol. 2017;4:e1327004 pubmed publisher
    ..Folate cycle stagnation via inhibition of its mitochondrial folate enzyme methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) greatly induced oxidative stress improving HCC cells' response to sorafenib...
  10. Petschner P, Gonda X, Baksa D, Eszlari N, Trivaks M, Juhasz G, et al. Genes Linking Mitochondrial Function, Cognitive Impairment and Depression are Associated with Endophenotypes Serving Precision Medicine. Neuroscience. 2018;370:207-217 pubmed publisher
  11. Christensen K, Patel H, Kuzmanov U, Mejia N, MacKenzie R. Disruption of the mthfd1 gene reveals a monofunctional 10-formyltetrahydrofolate synthetase in mammalian mitochondria. J Biol Chem. 2005;280:7597-602 pubmed
    ..This monofunctional synthetase completes the pathway for the production of formate from formyltetrahydrofolate in the mitochondria in our model of mammalian one-carbon folate metabolism in embryonic and transformed cells. ..
  12. Ma X, Yu J, Wu Z, Zhang Q, Liu Q, Wang H, et al. Replication of the MTHFD1L gene association with late-onset Alzheimer's disease in a Northern Han Chinese population. J Alzheimers Dis. 2012;29:521-5 pubmed publisher
    ..400; p < 0.001). Haplotype analysis revealed the "AC" haplotype increased the risk of developing LOAD (OR = 1.730; p = 0.015). Our findings support a role of MTHFD1L gene in LOAD. ..
  13. Lluís Ganella C, Lucas G, Subirana I, Senti M, Jimenez Conde J, Marrugat J, et al. Additive effect of multiple genetic variants on the risk of coronary artery disease. Rev Esp Cardiol. 2010;63:925-33 pubmed
    ..Cohort studies are needed to determine whether this genetic risk score can improve the predictive capacity or the risk classification of classical risk functions. ..
  14. McKnight A, Maxwell A, Fogarty D, Sadlier D, Savage D. Genetic analysis of coronary artery disease single-nucleotide polymorphisms in diabetic nephropathy. Nephrol Dial Transplant. 2009;24:2473-6 pubmed publisher
    ..002; combined P < 0.00001; OR = 1.54, 95% CI: 1.29-1.84). Our case-control data suggest that rs4420638, or a functional SNP in linkage disequilibrium with this SNP, may be associated with diabetic nephropathy. ..
  15. Eszlari N, Kovacs D, Petschner P, Pap D, Gonda X, Elliott R, et al. Distinct effects of folate pathway genes MTHFR and MTHFD1L on ruminative response style: a potential risk mechanism for depression. Transl Psychiatry. 2016;6:e745 pubmed publisher
    ..Further research should unravel whether the reversible metabolic effect of MTHFD1L is responsible for increased rumination or other long-term effects on brain development. ..
  16. Lee D, Xu I, Chiu D, Lai R, Tse A, Lan Li L, et al. Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma. J Clin Invest. 2017;127:1856-1872 pubmed publisher
    ..Taken together, our study identifies MTHFD1L in the folate cycle as an important metabolic pathway in cancer cells with the potential for therapeutic targeting. ..
  17. Fountoulakis M, Gulesserian T, Lubec G. Overexpression of C1-tetrahydrofolate synthase in fetal Down syndrome brain. J Neural Transm Suppl. 2003;:85-93 pubmed
    ..This may be of pathomechanistic relevance and thus extends and confirms the involvement of folate metabolism in trisomy 21. ..
  18. Hubacek J, Staněk V, Gebauerová M, Poledne R, Aschermann M, Skalická H, et al. Rs6922269 marker at the MTHFD1L gene predict cardiovascular mortality in males after acute coronary syndrome. Mol Biol Rep. 2015;42:1289-93 pubmed publisher
    ..001, OR 2.52, 95% CI 1.40-4.55, for AA vs. +G). We conclude, that rs6922269 variant at MTHFD1L gene could be an important prognostic factor for cardiovascular mortality in patients after ACS. ..
  19. Palmer B, Slow S, Ellis K, Pilbrow A, Skelton L, Frampton C, et al. Genetic polymorphism rs6922269 in the MTHFD1L gene is associated with survival and baseline active vitamin B12 levels in post-acute coronary syndromes patients. PLoS ONE. 2014;9:e89029 pubmed publisher
    ..MTHFD1L rs6922269 genotype is associated with active vitamin B12 levels at baseline and may be a marker of prognostic risk in patients with established coronary heart disease. ..
  20. Walkup A, Appling D. Enzymatic characterization of human mitochondrial C1-tetrahydrofolate synthase. Arch Biochem Biophys. 2005;442:196-205 pubmed
    ..The Km values for formate and ATP also are lowered when THF polyglutamates are used. The formate Km dropped 79-fold and the ATP Km dropped more than 5-fold when (6R,S)-H4-PteGlu5 was used as the substrate in place of (6R,S)-H4-PteGlu1. ..
  21. Ghazouani L, Khalifa S, Abboud N, Perret C, Nicaud V, Ben Khalfallah A, et al. Association of three polymorphisms selected from a genome-wide association study with coronary heart disease in the Tunisian population. J Thromb Thrombolysis. 2010;29:114-8 pubmed publisher
    ..The three SNPs previously reported to be associated with CHD were not replicated in our small sample. ..
  22. Minguzzi S, Selcuklu S, Spillane C, Parle McDermott A. An NTD-associated polymorphism in the 3' UTR of MTHFD1L can affect disease risk by altering miRNA binding. Hum Mutat. 2014;35:96-104 pubmed publisher
    ..These results reveal that the association of SNP rs7646 and NTD risk involves differences in microRNA regulation and, highlights the importance of genotype-dependent differential microRNA regulation in relation to human disease risk. ..
  23. Calvo S, Compton A, Hershman S, Lim S, Lieber D, Tucker E, et al. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Transl Med. 2012;4:118ra10 pubmed publisher
    ..The pathogenicity of two such genes, NDUFB3 and AGK, was supported by complementation studies and evidence from multiple patients, respectively. The results underscore the potential and challenges of deploying NGS in clinical settings. ..
  24. Ren R, Wang L, Fang R, Liu L, Wang Y, Tang H, et al. The MTHFD1L gene rs11754661 marker is associated with susceptibility to Alzheimer's disease in the Chinese Han population. J Neurol Sci. 2011;308:32-4 pubmed publisher
    ..829, 95% CI: 1.277-2.619, P=0.001), and the results were influenced by APOE status. Our data revealed that the allele (A) of the rs11754661 polymorphism within MTHFD1L gene may contribute to AD risk in the Chinese Han population. ..
  25. Ramirez Lorca R, Boada M, Antunez C, Lopez Arrieta J, Moreno Rey C, Hernandez I, et al. The MTHFD1L gene rs11754661 marker is not associated with Alzheimer's disease in a sample of the Spanish population. J Alzheimers Dis. 2011;25:47-50 pubmed publisher
    ..We have carried out an independent study of this genetic variant in 2467 individuals from Spain. We found no evidence of association between the MTHFD1L marker and susceptibility to Alzheimer's disease in our sample. ..
  26. Roder C, Peters V, Kasuya H, Nishizawa T, Takehara Y, Berg D, et al. Common genetic polymorphisms in moyamoya and atherosclerotic disease in Europeans. Childs Nerv Syst. 2011;27:245-52 pubmed publisher
    ..Further analyses in larger European cohorts and replication in patients of different ethnicity may lead to possible early detection of patients at risk for developing MMD and subsequently to future causative therapies. ..
  27. Zhang R, Cao L, Wang Y, Fang Y, Zhao L, Li W, et al. A unique methylation pattern co-segregates with neural tube defect statuses in Han Chinese pedigrees. Neurol Sci. 2017;38:2153-2164 pubmed publisher
    ..Although the genetics of NTD are likely complex, epigenetic changes may concentrate in certain key pathways. ..
  28. Kim D, Lee S, Won H, Kim S, Kim M, Kim H, et al. A genome-wide association study identifies novel loci associated with susceptibility to chronic myeloid leukemia. Blood. 2011;117:6906-11 pubmed publisher
    ..1 was validated in both Korean and European cohorts, whereas 17p11.1 was validated only in the Korean cohort. These findings suggest that genetic variants of 6q25.1 and 17p11.1 may predispose one to the development of CML. ..
  29. Christensen K, MacKenzie R. Mitochondrial methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and formyltetrahydrofolate synthetases. Vitam Horm. 2008;79:393-410 pubmed publisher
    ..This review discusses the properties and functions of these mitochondrial proteins and their role in supporting cytosolic purine synthesis during embryonic development and in cells undergoing rapid growth. ..
  30. Zhu S, Wang L, Cao Z, Wang J, Jing M, Xia Z, et al. Inducible CYP4F12 enhances Hepatitis C virus infection via association with viral nonstructural protein 5B. Biochem Biophys Res Commun. 2016;471:95-102 pubmed publisher
    ..Our results showed that HCV infection induced expression of CYP4F12 protein, which bound to the HCV replication complex to facilitate viral replication. ..