MTHFD1L Gene

Name	methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like
Description	The protein encoded by this gene is involved in the synthesis of tetrahydrofolate (THF) in the mitochondrion. THF is important in the de novo synthesis of purines and thymidylate and in the regeneration of methionine from homocysteine. Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jun 2011]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMTHFD1L encodes the mitochondrial isoform of C1‐tetrahydrofolate (THF) synthase, an enzyme integral to the folate one‐carbon metabolism pathway. Biochemical characterization has revealed that, in contrast to its cytoplasmic counterpart, the mitochondrial enzyme predominantly exhibits 10‐formyl‐THF synthetase activity. This activity facilitates the conversion of substrates into formylated folate derivatives that are essential for nucleotide biosynthesis, methionine production, and the maintenance of mitochondrial NADPH levels necessary to counterbalance oxidative stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic alterations in MTHFD1L can influence its functional output through effects on splicing efficiency and post‐transcriptional regulation. In particular, variants such as a triallelic deletion/insertion polymorphism have been shown to modulate alternative splicing of its mRNA, with differential binding of microRNAs (for example, miR‐9 and miR‐197) affecting gene expression. These changes in MTHFD1L expression and activity are associated with developmental and neurological conditions—including neural tube defects, Alzheimer’s disease, and even cognitive and mood-related phenotypes—likely through alterations in homocysteine clearance and methionine synthesis that are critical for normal neurodevelopment and brain function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn oncology, up‐regulation of MTHFD1L has been observed in several tumor types, where its activity appears to promote cancer cell growth and survival. Increased expression—often mediated by redox‐sensitive transcription factors like NRF2—enables enhanced production of NADPH, which not only supports biosynthetic processes required for rapid proliferation but also helps cancer cells manage heightened oxidative stress. Moreover, elevated MTHFD1L has been implicated in the progression of hepatocellular carcinoma, esophageal squamous cell carcinoma, and osteosarcoma, with effects that include stimulation of the cell cycle and activation of proliferative signaling cascades such as the AKT/mTOR pathway. Such findings point to MTHFD1L as a potential target for therapeutic intervention in cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the cardiovascular domain, emerging evidence links genetic variants in MTHFD1L to coronary artery disease and myocardial infarction risk. Although the precise mechanistic contributions remain to be fully elucidated, these observations suggest that perturbations in mitochondrial folate metabolism may influence vascular homeostasis and atherosclerotic processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Priya Prasannan, Schuyler Pike, Kun Peng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human mitochondrial C1-tetrahydrofolate synthase: gene structure, tissue distribution of the mRNA, and immunolocalization in Chinese hamster ovary calls."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M304319200"}], "href": "https://doi.org/10.1074/jbc.M304319200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12937168"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12937168"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Addie S Walkup, Dean R Appling "}, {"type": "b", "children": [{"type": "t", "text": "Enzymatic characterization of human mitochondrial C1-tetrahydrofolate synthase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arch Biochem Biophys (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.abb.2005.08.007"}], "href": "https://doi.org/10.1016/j.abb.2005.08.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16171773"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16171773"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Anne Parle-McDermott, Faith Pangilinan, Kirsty K O'Brien, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A common variant in MTHFD1L is associated with neural tube defects and mRNA splicing efficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.21109"}], "href": "https://doi.org/10.1002/humu.21109"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19777576"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19777576"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Adam C Naj, Gary W Beecham, Eden R Martin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dementia revealed: novel chromosome 6 locus for late-onset Alzheimer disease provides genetic evidence for folate-pathway abnormalities."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1001130"}], "href": "https://doi.org/10.1371/journal.pgen.1001130"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20885792"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20885792"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Ru-Jing Ren, Li-Ling Wang, Rong Fang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The MTHFD1L gene rs11754661 marker is associated with susceptibility to Alzheimer's disease in the Chinese Han population."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurol Sci (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jns.2011.06.036"}], "href": "https://doi.org/10.1016/j.jns.2011.06.036"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21741665"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21741665"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Xiao-Ying Ma, Jin-Tai Yu, Zhong-Chen Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Replication of the MTHFD1L gene association with late-onset Alzheimer's disease in a Northern Han Chinese population."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Alzheimers Dis (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3233/JAD-2011-111847"}], "href": "https://doi.org/10.3233/JAD-2011-111847"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22330827"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22330827"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Stefano Minguzzi, S Duygu Selcuklu, Charles Spillane, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An NTD-associated polymorphism in the 3' UTR of MTHFD1L can affect disease risk by altering miRNA binding."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.22459"}], "href": "https://doi.org/10.1002/humu.22459"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24123340"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24123340"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "N Eszlari, D Kovacs, P Petschner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Distinct effects of folate pathway genes MTHFR and MTHFD1L on ruminative response style: a potential risk mechanism for depression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Transl Psychiatry (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/tp.2016.19"}], "href": "https://doi.org/10.1038/tp.2016.19"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26926881"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26926881"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Stefano Minguzzi, Anne M Molloy, Kirke Peadar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genotyping of a tri-allelic polymorphism by a novel melting curve assay in MTHFD1L: an association study of nonsyndromic Cleft in Ireland."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Med Genet (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2350-13-29"}], "href": "https://doi.org/10.1186/1471-2350-13-29"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22520921"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22520921"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Derek Lee, Iris Ming-Jing Xu, David Kung-Chun Chiu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI90253"}], "href": "https://doi.org/10.1172/JCI90253"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28394261"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28394261"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Yu-Shang Yang, Yong Yuan, Wei-Peng Hu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The role of mitochondrial folate enzyme MTHFD1L in esophageal squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Scand J Gastroenterol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/00365521.2017.1407440"}], "href": "https://doi.org/10.1080/00365521.2017.1407440"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29171320"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29171320"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Lei Wang, Ya Yang, Xiu-Mei Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MTHFD1L as a folate cycle enzyme correlates with prognostic outcome and its knockdown impairs cell invasive behaviors in osteosarcoma via mediating the AKT/mTOR pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Recept Signal Transduct Res (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/10799893.2020.1769658"}], "href": "https://doi.org/10.1080/10799893.2020.1769658"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32456526"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32456526"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Nuzhat Sial, Jalil Ur Rehman, Saba Saeed, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Integrative analysis reveals methylenetetrahydrofolate dehydrogenase 1-like as an independent shared diagnostic and prognostic biomarker in five different human cancers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biosci Rep (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BSR20211783"}], "href": "https://doi.org/10.1042/BSR20211783"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34908119"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34908119"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Barry R Palmer, Sandy Slow, Katrina L Ellis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic polymorphism rs6922269 in the MTHFD1L gene is associated with survival and baseline active vitamin B12 levels in post-acute coronary syndromes patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0089029"}], "href": "https://doi.org/10.1371/journal.pone.0089029"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24618918"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24618918"}]}]}]}
Synonyms	DJ292B18.2, MTC1THFS, FTHFSDC1
Proteins	C1TM_HUMAN
NCBI Gene ID	25902
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

MTHFD1L has 9,671 functional associations with biological entities spanning 9 categories (molecular profile, organism, functional term, phrase or reference, chemical, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 123 datasets.

Click the + buttons to view associations for MTHFD1L from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

MTHFD1L Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by MTHFD1L gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of MTHFD1L gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of MTHFD1L gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of MTHFD1L gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of MTHFD1L gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of MTHFD1L gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of MTHFD1L gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of MTHFD1L gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of MTHFD1L gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of MTHFD1L gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of MTHFD1L gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with MTHFD1L protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with MTHFD1L gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of MTHFD1L gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of MTHFD1L gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of MTHFD1L gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CM4AI U2OS Cell Map Protein Localization Assemblies	assemblies containing MTHFD1L protein from integrated AP-MS and IF data from the CM4AI U2OS Cell Map Protein Localization Assemblies dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing MTHFD1L protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing MTHFD1L protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with MTHFD1L protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with MTHFD1L protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of MTHFD1L gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with MTHFD1L gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with MTHFD1L gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with MTHFD1L gene/protein from the curated CTD Gene-Disease Associations dataset.
	dbGAP Gene-Trait Associations	traits associated with MTHFD1L gene in GWAS and other genetic association datasets from the dbGAP Gene-Trait Associations dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by MTHFD1L gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores	diseases associated with MTHFD1L gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with MTHFD1L gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with MTHFD1L gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with MTHFD1L gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with MTHFD1L gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with MTHFD1L gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at MTHFD1L gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of MTHFD1L gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of MTHFD1L gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing MTHFD1L from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD Gene-Disease Associations	diseases associated with MTHFD1L gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.
	GeneRIF Biological Term Annotations	biological terms co-occuring with MTHFD1L gene in literature-supported statements describing functions of genes from the GeneRIF Biological Term Annotations dataset.
	GeneSigDB Published Gene Signatures	PubMedIDs of publications reporting gene signatures containing MTHFD1L from the GeneSigDB Published Gene Signatures dataset.