MTRR Gene

Name	5-methyltetrahydrofolate-homocysteine methyltransferase reductase
Description	This gene encodes a member of the ferredoxin-NADP(+) reductase (FNR) family of electron transferases. This protein functions in the synthesis of methionine by regenerating methionine synthase to a functional state. Because methionine synthesis requires methyl-group transfer by a folate donor, activity of the encoded enzyme is important for folate metabolism and cellular methylation. Mutations in this gene can cause homocystinuria-megaloblastic anemia, cbl E type. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2015]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMethionine synthase reductase (MTRR) is a key enzyme in folate metabolism that serves to reactivate methionine synthase by converting its oxidized, inactive form back into its active methylcobalamin‐bound state. In doing so, MTRR ensures the continuous remethylation of homocysteine to methionine, a step that is essential for maintaining proper one‐carbon metabolism, DNA methylation and synthesis, and stable plasma homocysteine levels. Studies have demonstrated that MTRR’s catalytic properties and interactions with both natural and artificial electron acceptors are sensitive to amino acid substitutions—such as the common A66G (I22M) variant—which can necessitate higher enzyme ratios for maximal activation of methionine synthase."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": ""}, {"type": "p", "children": [{"type": "t", "text": "\nEpidemiologic investigations have linked MTRR genetic polymorphisms with altered disease risks. For example, variant MTRR genotypes—often studied in the context of the A66G substitution—have been associated with modest elevations in plasma homocysteine and with increased susceptibility to congenital malformations such as spina bifida and Down syndrome, as well as influencing cancer risk. These studies underscore how genetic variation in MTRR, in combination with other folate‐related polymorphisms and nutritional factors (e.g., folate and B‐vitamin status), can modulate remethylation efficiency and thereby contribute to multifactorial conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "12"}]}, {"type": "t", "text": ""}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, pharmacogenomic and functional studies have evaluated how MTRR variants affect treatment outcomes and other physiological processes. Alterations in MTRR activity have been implicated in modulating sensitivity to antifolate drugs such as methotrexate, influencing DNA methylation profiles in infants, and even contributing to reproductive outcomes and cardiovascular risk. These findings, emerging from investigations of diverse populations and clinical models, highlight that the efficiency of methionine synthase reductive repair is not only fundamental for metabolic homeostasis but also a potential modifier of response to nutritional and pharmacologic interventions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "21"}]}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "L D Botto, Q Yang "}, {"type": "b", "children": [{"type": "t", "text": "5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Epidemiol (2000)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/oxfordjournals.aje.a010290"}], "href": "https://doi.org/10.1093/oxfordjournals.aje.a010290"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "10791559"}], "href": "https://pubmed.ncbi.nlm.nih.gov/10791559"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "D J Gaughan, L A Kluijtmans, S Barbaux, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Atherosclerosis (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0021-9150(00)00739-5"}], "href": "https://doi.org/10.1016/s0021-9150(00"}, {"type": "t", "text": "00739-5) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11472746"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11472746"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Horatiu Olteanu, Troy Munson, Ruma Banerjee "}, {"type": "b", "children": [{"type": "t", "text": "Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi020536s"}], "href": "https://doi.org/10.1021/bi020536s"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12416982"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12416982"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Leo A J Kluijtmans, Ian S Young, Colin A Boreham, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Genetic and non-genetic influences during pregnancy on infant global and site specific DNA methylation: role for folate gene variants and vitamin B12."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0033290"}], "href": "https://doi.org/10.1371/journal.pone.0033290"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22479380"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22479380"}]}]}]}
Synonyms	MSR, CBLE
Proteins	MTRR_HUMAN
NCBI Gene ID	4552
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

MTRR has 7,364 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, disease, phenotype or trait, functional term, phrase or reference, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 131 datasets.

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

If available, associations are ranked by standardized value

Harmonizome 3.0

MTRR 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 MTRR 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 MTRR 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 MTRR 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 MTRR 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 MTRR 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 MTRR 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 MTRR gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of MTRR gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of MTRR 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 MTRR gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of MTRR gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of MTRR 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 MTRR gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with MTRR protein from the CCLE Cell Line Proteomics dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of MTRR gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of MTRR 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 MTRR gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations	phenotypes associated with MTRR gene from the curated ClinVar Gene-Phenotype Associations dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with MTRR gene from the curated ClinVar Gene-Phenotype Associations 2025 dataset.
	CM4AI KOLF21J CRISPRi Gene Perturbation Atlas	gene perturbations changing expression of MTRR gene from the CM4AI KOLF21J CRISPRi Gene Perturbation Atlas dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of MTRR gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing MTRR protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing MTRR protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing MTRR protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores 2025	cellular components containing MTRR protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with MTRR 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 MTRR 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 MTRR gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with MTRR gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with MTRR gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with MTRR gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of MTRR protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by MTRR gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DGIdb Drug Targets 2026	interacting drugs for MTRR protein from the DGIdb Drug Targets 2026 dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores	diseases involving MTRR gene from the DISEASES Curated Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores 2025	diseases involving MTRR gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with MTRR 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 MTRR 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 MTRR 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 MTRR gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.