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MTHFR methylenetetrahydrofolate reductase [ Homo sapiens (human) ]

Gene ID: 4524, updated on 3-Apr-2024

Summary

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Official Symbol
MTHFRprovided by HGNC
Official Full Name
methylenetetrahydrofolate reductaseprovided by HGNC
Primary source
HGNC:HGNC:7436
See related
Ensembl:ENSG00000177000 MIM:607093; AllianceGenome:HGNC:7436
Gene type
protein coding
RefSeq status
REVIEWED
Organism
Homo sapiens
Lineage
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Summary
The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]
Expression
Ubiquitous expression in lung (RPKM 7.5), thyroid (RPKM 7.2) and 25 other tissues See more
Orthologs
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Genomic context

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See MTHFR in Genome Data Viewer
Location:
1p36.22
Exon count:
13
Annotation release Status Assembly Chr Location
RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 1 NC_000001.11 (11785723..11805964, complement)
RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 1 NC_060925.1 (11329802..11350048, complement)
105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 1 NC_000001.10 (11845780..11866021, complement)

Chromosome 1 - NC_000001.11Genomic Context describing neighboring genes Neighboring gene atrophin-1-like Neighboring gene chromosome 1 open reading frame 167 Neighboring gene C1orf167 antisense RNA 1 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr1:11847781-11848588 Neighboring gene ReSE screen-validated silencer GRCh37_chr1:11851353-11851865 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr1:11860626-11861224 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr1:11862804-11863700 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr1:11863701-11864596 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 272 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 273 Neighboring gene H3K27ac hESC enhancer GRCh37_chr1:11865893-11866878 Neighboring gene chloride voltage-gated channel 6 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 178 Neighboring gene NPPA antisense RNA 1 Neighboring gene VISTA enhancer hs2123 Neighboring gene natriuretic peptide A

Genomic regions, transcripts, and products

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Go to nucleotide: Graphics FASTA GenBank

Expression

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  • Project title: HPA RNA-seq normal tissues
  • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
  • BioProject: PRJEB4337
  • Publication: PMID 24309898
  • Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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Related articles in PubMed

  1. Effects of folic acid supplementation on chronic atrophic gastritis based on MTHFR C677T polymorphism. Kong S, et al. Medicine (Baltimore), 2023 Jun 16. PMID 37327296, Free PMC Article
  2. Plasma thiol levels and methylenetetrahydrofolate reductase gene c.665C > T and c.1286A > C variants affect fibrin clot properties in Polish venous thromboembolic patients. Klajmon A, et al. Mol Genet Metab, 2023 Jul. PMID 37302269
  3. Dual effect of methylene-tetrahydrofolate reductase and angiotensinconverting enzyme gene polymorphisms on the risk of acute ischemic stroke. Karakus N, et al. J Genet, 2023. PMID 37204128
  4. Maternal pre-pregnancy BMI, MTHFR polymorphisms, and the risk of adverse pregnancy outcomes in pregnant women from South China: a retrospective cohort study. Gu C, et al. BMC Pregnancy Childbirth, 2023 Apr 27. PMID 37106323, Free PMC Article
  5. Methylenetetrahydrofolate reductase polymorphisms and elevated plasma homocysteine levels in small vessel disease. Chen L, et al. Brain Behav, 2023 May. PMID 36978223, Free PMC Article

See all (3805) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. [Analysis of 9 patients with adolescence-onset methylenetetrahydrofolate reductase deficiency].
    Title: [Analysis of 9 patients with adolescence-onset methylenetetrahydrofolate reductase deficiency].
  2. Interaction effects of MTHFR C677T and A1298C polymorphisms with maternal glycated haemoglobin levels on adverse birth outcomes.
    Title: Interaction effects of MTHFR C677T and A1298C polymorphisms with maternal glycated haemoglobin levels on adverse birth outcomes.
  3. Association between MTHFR C677T Gene Polymorphisms and the Efficacy of Vitamin Therapy in lowering Homocysteine Levels among Stroke Patients with Hyperhomocysteinemia.
    Title: Association between MTHFR C677T Gene Polymorphisms and the Efficacy of Vitamin Therapy in lowering Homocysteine Levels among Stroke Patients with Hyperhomocysteinemia.
  4. Association between maternal diet, smoking, and the placenta MTHFR 677C/T genotype and global placental DNA methylation.
    Title: Association between maternal diet, smoking, and the placenta MTHFR 677C/T genotype and global placental DNA methylation.
  5. Congenital septal defects in Karachi, Pakistan: an update of mutational screening by high-resolution melting (HRM) analysis of MTHFR C677T.
    Title: Congenital septal defects in Karachi, Pakistan: an update of mutational screening by high-resolution melting (HRM) analysis of MTHFR C677T.
  6. Relationship between methylenetetrahydrofolate reductase C677T gene polymorphism and neutrophil gelatinase-associated lipocalin in early renal injury in H-type hypertension.
    Title: Relationship between methylenetetrahydrofolate reductase C677T gene polymorphism and neutrophil gelatinase-associated lipocalin in early renal injury in H-type hypertension.
  7. Association of methylenetetrahydrofolate reductase gene variant C677T and folate levels in non-syndromic cleft lip/palate among Sindhi, Pakistani population.
    Title: Association of methylenetetrahydrofolate reductase gene variant C677T and folate levels in non-syndromic cleft lip/palate among Sindhi, Pakistani population.
  8. A Comprehensive Investigation into the Association Between Mthfr C677t, A1298c, and Ace I/D Variants and Risk of Migraine: an Updated Meta-Analysis of Genetic Association Studies with Trial Sequential Analysis and Meta-Regression.
    Title: A Comprehensive Investigation into the Association Between Mthfr C677t, A1298c, and Ace I/D Variants and Risk of Migraine: an Updated Meta-Analysis of Genetic Association Studies with Trial Sequential Analysis and Meta-Regression.
  9. Association study between genetic polymorphisms in MTHFR and stroke susceptibility in Egyptian population: a case-control study.
    Title: Association study between genetic polymorphisms in MTHFR and stroke susceptibility in Egyptian population: a case-control study.
  10. MTHFR and risk of stroke and heart disease in a low-folate population: a prospective study of 156 000 Chinese adults.
    Title: MTHFR and risk of stroke and heart disease in a low-folate population: a prospective study of 156 000 Chinese adults.
Submit: New GeneRIF Correction See all GeneRIFs (2582)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description Tests
Homocystinuria due to methylene tetrahydrofolate reductase deficiency
MedGen: C1856058 OMIM: 236250 GeneReviews: Not available
Compare labs
Neural tube defects, folate-sensitive
MedGen: C1866558 OMIM: 601634 GeneReviews: Not available
Compare labs
Schizophrenia
MedGen: C0036341 OMIM: 181500 GeneReviews: Not available
Compare labs
Thrombophilia due to thrombin defect
MedGen: C3160733 OMIM: 188050 GeneReviews: Prothrombin Thrombophilia
Compare labs

EBI GWAS Catalog

Description
Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease.
EBI GWAS Catalog
Genome-wide association study identifies eight loci associated with blood pressure.
EBI GWAS Catalog
Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.
EBI GWAS Catalog
Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway.
EBI GWAS Catalog
Novel associations of CPS1, MUT, NOX4, and DPEP1 with plasma homocysteine in a healthy population: a genome-wide evaluation of 13 974 participants in the Women's Genome Health Study.
EBI GWAS Catalog
Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry.
EBI GWAS Catalog

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Genotypes

Pathways from PubChem

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Interactions

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Products Interactant Other Gene Complex Source Pubs Description

General gene information

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Markers

Homology

Gene Ontology Provided by GOA

Function Evidence Code Pubs
enables FAD binding IBA
Inferred from Biological aspect of Ancestor
more info
  
enables NADP binding IEA
Inferred from Electronic Annotation
more info
  
enables flavin adenine dinucleotide binding IDA
Inferred from Direct Assay
more info
 PubMed 
enables methylenetetrahydrofolate reductase (NAD(P)H) activity IBA
Inferred from Biological aspect of Ancestor
more info
  
enables methylenetetrahydrofolate reductase (NAD(P)H) activity IDA
Inferred from Direct Assay
more info
 PubMed 
enables methylenetetrahydrofolate reductase (NAD(P)H) activity IGI
Inferred from Genetic Interaction
more info
 PubMed 
enables methylenetetrahydrofolate reductase (NAD(P)H) activity IMP
Inferred from Mutant Phenotype
more info
 PubMed 
enables methylenetetrahydrofolate reductase NADPH activity IEA
Inferred from Electronic Annotation
more info
  
enables modified amino acid binding IDA
Inferred from Direct Assay
more info
 PubMed 
enables protein-containing complex binding IPI
Inferred from Physical Interaction
more info
 PubMed 
Process Evidence Code Pubs
involved_in S-adenosylmethionine metabolic process IEA
Inferred from Electronic Annotation
more info
  
acts_upstream_of heterochromatin organization IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in homocysteine metabolic process IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in methionine biosynthetic process IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in methionine metabolic process IGI
Inferred from Genetic Interaction
more info
 PubMed 
acts_upstream_of neural tube closure IMP
Inferred from Mutant Phenotype
more info
 PubMed 
acts_upstream_of neural tube closure NAS
Non-traceable Author Statement
more info
 PubMed 
involved_in response to amino acid IEA
Inferred from Electronic Annotation
more info
  
involved_in response to folic acid IEA
Inferred from Electronic Annotation
more info
  
involved_in response to hypoxia IEA
Inferred from Electronic Annotation
more info
  
involved_in response to interleukin-1 IEA
Inferred from Electronic Annotation
more info
  
involved_in response to vitamin B2 IEA
Inferred from Electronic Annotation
more info
  
involved_in response to xenobiotic stimulus IEA
Inferred from Electronic Annotation
more info
  
involved_in tetrahydrofolate interconversion IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in tetrahydrofolate interconversion IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in tetrahydrofolate interconversion IEA
Inferred from Electronic Annotation
more info
  
involved_in tetrahydrofolate interconversion IGI
Inferred from Genetic Interaction
more info
 PubMed 
involved_in tetrahydrofolate interconversion IMP
Inferred from Mutant Phenotype
more info
 PubMed 
Component Evidence Code Pubs
located_in cytosol TAS
Traceable Author Statement
more info
  

General protein information

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Preferred Names
methylenetetrahydrofolate reductase (NADPH)
Names
5,10-methylenetetrahydrofolate reductase (NADPH)
methylenetetrahydrofolate reductase (NAD(P)H)
NP_001317287.1
NP_001397679.1
NP_005948.3
XP_005263519.1
XP_005263520.1
XP_011539798.1
XP_016856817.1
XP_047277130.1
XP_047277134.1
XP_047277135.1
XP_047277136.1
XP_047277137.1
XP_054192675.1
XP_054192676.1
XP_054192677.1
XP_054192678.1
XP_054192679.1
XP_054192680.1
XP_054192681.1
XP_054192682.1

NCBI Reference Sequences (RefSeq)

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NEW Try the new Transcript table

RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

  1. NG_013351.1 RefSeqGene

    Range
    5001..25374
    Download
    GenBank, FASTA, Sequence Viewer (Graphics), LRG_726

mRNA and Protein(s)

  1. NM_001330358.2 → NP_001317287.1  methylenetetrahydrofolate reductase (NADPH) isoform 1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (1) encodes the longer isoform (1).
    Source sequence(s)
    AL953897
    Consensus CDS
    CCDS81262.1
    UniProtKB/TrEMBL
    Q59GJ6
    Related
    ENSP00000365767.3, ENST00000376583.7

  2. NM_001410750.1 → NP_001397679.1  methylenetetrahydrofolate reductase (NADPH) isoform 3

    Status: REVIEWED

    Source sequence(s)
    AL953897
    Consensus CDS
    CCDS90864.1
    UniProtKB/TrEMBL
    Q5SNW7
    Related
    ENSP00000398908.3, ENST00000423400.7

  3. NM_005957.5 → NP_005948.3  methylenetetrahydrofolate reductase (NADPH) isoform 2

    See identical proteins and their annotated locations for NP_005948.3

    Status: REVIEWED

    Description
    Transcript Variant: This variant (2) differs in the 5' UTR and coding sequence compared to variant 1. The resulting isoform (2) is shorter at the N-terminus compared to isoform 1.
    Source sequence(s)
    AB209113, AJ237672, AL953897, AY046560, BC053509
    Consensus CDS
    CCDS137.1
    UniProtKB/Swiss-Prot
    B2R7A6, P42898, Q5SNW6, Q5SNW9, Q7Z6M6, Q8IU73, Q9UQR2
    UniProtKB/TrEMBL
    A0A286YF17
    Related
    ENSP00000365775.3, ENST00000376590.9
    Conserved Domains (1) summary
    cl00246
    Location:60 → 626
    MTHFR; Methylenetetrahydrofolate reductase (MTHFR). 5,10-Methylenetetrahydrofolate is reduced to 5-methyltetrahydrofolate by methylenetetrahydrofolate reductase, a cytoplasmic, NAD(P)-dependent enzyme. 5-methyltetrahydrofolate is utilized by methionine synthase ...

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

  1. NC_000001.11 Reference GRCh38.p14 Primary Assembly

    Range
    11785723..11805964 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_047421181.1 → XP_047277137.1  methylenetetrahydrofolate reductase (NADPH) isoform X6

  2. XM_005263462.5 → XP_005263519.1  methylenetetrahydrofolate reductase (NADPH) isoform X3

    See identical proteins and their annotated locations for XP_005263519.1

    UniProtKB/Swiss-Prot
    B2R7A6, P42898, Q5SNW6, Q5SNW9, Q7Z6M6, Q8IU73, Q9UQR2
    UniProtKB/TrEMBL
    A0A286YF17
    Conserved Domains (1) summary
    cl00246
    Location:60 → 626
    MTHFR; Methylenetetrahydrofolate reductase (MTHFR). 5,10-Methylenetetrahydrofolate is reduced to 5-methyltetrahydrofolate by methylenetetrahydrofolate reductase, a cytoplasmic, NAD(P)-dependent enzyme. 5-methyltetrahydrofolate is utilized by methionine synthase ...

  3. XM_047421179.1 → XP_047277135.1  methylenetetrahydrofolate reductase (NADPH) isoform X5

    UniProtKB/TrEMBL
    A0A286YFD0
    Related
    ENSP00000493098.1, ENST00000641407.1

  4. XM_047421180.1 → XP_047277136.1  methylenetetrahydrofolate reductase (NADPH) isoform X6

    Related
    ENSP00000493262.1, ENST00000641446.1

  5. XM_047421178.1 → XP_047277134.1  methylenetetrahydrofolate reductase (NADPH) isoform X3

    UniProtKB/Swiss-Prot
    B2R7A6, P42898, Q5SNW6, Q5SNW9, Q7Z6M6, Q8IU73, Q9UQR2
    Related
    ENSP00000365777.1, ENST00000376592.6

  6. XM_047421174.1 → XP_047277130.1  methylenetetrahydrofolate reductase (NADPH) isoform X2

  7. XM_011541496.4 → XP_011539798.1  methylenetetrahydrofolate reductase (NADPH) isoform X1

    UniProtKB/TrEMBL
    Q59GJ6
    Conserved Domains (1) summary
    cl00246
    Location:101 → 625
    MTHFR; Methylenetetrahydrofolate reductase (MTHFR). 5,10-Methylenetetrahydrofolate is reduced to 5-methyltetrahydrofolate by methylenetetrahydrofolate reductase, a cytoplasmic, NAD(P)-dependent enzyme. 5-methyltetrahydrofolate is utilized by methionine synthase ...

  8. XM_017001328.3 → XP_016856817.1  methylenetetrahydrofolate reductase (NADPH) isoform X4

    UniProtKB/TrEMBL
    A0A286YF17

  9. XM_005263463.5 → XP_005263520.1  methylenetetrahydrofolate reductase (NADPH) isoform X7

    UniProtKB/TrEMBL
    A0A286YF17
    Conserved Domains (1) summary
    cl00246
    Location:1 → 544
    MTHFR; Methylenetetrahydrofolate reductase (MTHFR). 5,10-Methylenetetrahydrofolate is reduced to 5-methyltetrahydrofolate by methylenetetrahydrofolate reductase, a cytoplasmic, NAD(P)-dependent enzyme. 5-methyltetrahydrofolate is utilized by methionine synthase ...

Alternate T2T-CHM13v2.0

Genomic

  1. NC_060925.1 Alternate T2T-CHM13v2.0

    Range
    11329802..11350048 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_054336702.1 → XP_054192677.1  methylenetetrahydrofolate reductase (NADPH) isoform X3

  2. XM_054336707.1 → XP_054192682.1  methylenetetrahydrofolate reductase (NADPH) isoform X7

  3. XM_054336706.1 → XP_054192681.1  methylenetetrahydrofolate reductase (NADPH) isoform X6

  4. XM_054336704.1 → XP_054192679.1  methylenetetrahydrofolate reductase (NADPH) isoform X5

  5. XM_054336705.1 → XP_054192680.1  methylenetetrahydrofolate reductase (NADPH) isoform X6

  6. XM_054336701.1 → XP_054192676.1  methylenetetrahydrofolate reductase (NADPH) isoform X2

  7. XM_054336700.1 → XP_054192675.1  methylenetetrahydrofolate reductase (NADPH) isoform X1

  8. XM_054336703.1 → XP_054192678.1  methylenetetrahydrofolate reductase (NADPH) isoform X4

Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
P42898.3 GenPept UniProtKB/Swiss-Prot:P42898

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