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MTHFR methylenetetrahydrofolate reductase [ Homo sapiens (human) ]

Gene ID: 4524, updated on 2-Nov-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_2024_08 current GRCh38.p14 (GCF_000001405.40) 1 NC_000001.11 (11785723..11805964, complement)
RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 1 NC_060925.1 (11329802..11350048, complement)
RS_2024_09 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 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. Association of tagging SNPs in the MTHFR gene with risk of type 2 diabetes mellitus and serum homocysteine levels in a Chinese population. Wang H, et al. Dis Markers, 2014. PMID 25165408, Free PMC Article
  2. A lower degree of PBMC L1 methylation in women with lower folate status may explain the MTHFR C677T polymorphism associated higher risk of CIN in the US post folic acid fortification era. Badiga S, et al. PLoS One, 2014. PMID 25302494, Free PMC Article
  3. Ethnic variation of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate-reductase (MTHFR) gene in southwestern Mexico. Antonio-Véjar V, et al. Genet Mol Res, 2014 Sep 29. PMID 25299110
  4. A cross-sectional study to find out the relationship of methylenetetrahydrofolate reductase (MTHFR) C677T genotype with plasma levels of folate and total homocysteine by daily folate intake in Japanese. Fukuda N, et al. J Nutr Sci Vitaminol (Tokyo), 2014. PMID 25297611
  5. Methylenetetrahydrofolate reductase gene germ-line C677T and A1298C SNPs are associated with colorectal cancer risk in the Turkish population. Ozen F, et al. Asian Pac J Cancer Prev, 2014. PMID 25292054

See all (1000) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. Homozygous MTHFR C667T carriers </=45 years old develop central retinal vein occlusion five years earlier than wild type.
    Title: Homozygous MTHFR C667T carriers ≤45 years old develop central retinal vein occlusion five years earlier than wild type.
  2. Genetic association and computational analysis of MTHFR gene polymorphisms rs1801131 and rs1801133 with breast cancer in the Bangladeshi population.
    Title: Genetic association and computational analysis of MTHFR gene polymorphisms rs1801131 and rs1801133 with breast cancer in the Bangladeshi population.
  3. The MTHFR C677T/A1298C polymorphism is associated with increased risk of microangiopathy in type 2 diabetes mellitus: A systematic review and meta-analysis.
    Title: The MTHFR C677T/A1298C polymorphism is associated with increased risk of microangiopathy in type 2 diabetes mellitus: A systematic review and meta-analysis.
  4. Epigenetic alterations in preeclampsia: a focus on microRNA149 and tetrahydrofolate reductase gene polymorphisms in Egyptian women.
    Title: Epigenetic alterations in preeclampsia: a focus on microRNA149 and tetrahydrofolate reductase gene polymorphisms in Egyptian women.
  5. Association of Methylenetetrahydrofolate Reductase rs1801133 Polymorphism with osteoporosis and fracture risk in Taiwan.
    Title: Association of Methylenetetrahydrofolate Reductase rs1801133 Polymorphism with osteoporosis and fracture risk in Taiwan.
  6. Clinical characteristics and thrombophilia associated gene variants in Egyptians with unprovoked venous thromboembolism: three centers experience.
    Title: Clinical characteristics and thrombophilia associated gene variants in Egyptians with unprovoked venous thromboembolism: three centers experience.
  7. The Association of Plasma Homocysteine Concentrations with a 10-Year Risk of All-Cause and Cardiovascular Mortality in a Community-Based Chinese Population.
    Title: The Association of Plasma Homocysteine Concentrations with a 10-Year Risk of All-Cause and Cardiovascular Mortality in a Community-Based Chinese Population.
  8. The methylenetetrahydrofolate reductase C677T and A1298C genetic polymorphisms and plasma homocysteine in Alzheimer's disease in an Algerian population.
    Title: The methylenetetrahydrofolate reductase C677T and A1298C genetic polymorphisms and plasma homocysteine in Alzheimer's disease in an Algerian population.
  9. MTHFR 677 C > T Gene Polymorphism is Associated with Large for Gestational Age Infants.
    Title: MTHFR 677 C > T Gene Polymorphism is Associated with Large for Gestational Age Infants.
  10. SERPINE1 and MTHFR genetic variants in patients with embolic stroke of undetermined source: links with fibrin clot properties.
    Title: SERPINE1 and MTHFR genetic variants in patients with embolic stroke of undetermined source: links with fibrin clot properties.
Submit: New GeneRIF Correction See all GeneRIFs (2608)

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: C1856061 OMIM: 236250 GeneReviews: Not available
not available
Neural tube defects, folate-sensitive
MedGen: C1866558 OMIM: 601634 GeneReviews: Not available
not available
Schizophrenia
MedGen: C0036341 OMIM: 181500 GeneReviews: Not available
not available
Thrombophilia due to thrombin defect
MedGen: C3160733 OMIM: 188050 GeneReviews: Prothrombin Thrombophilia
not available

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 binding IPI
Inferred from Physical Interaction
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_2024_08

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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