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    MTHFR methylenetetrahydrofolate reductase [ Homo sapiens (human) ]

    Gene ID: 4524, updated on 27-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
    mouse all
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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
    • 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. MTHFR polymorphisms and serum cobalamin affect plasma homocysteine concentrations differentially in females and males. Nilsson TK, et al. Mol Med Rep, 2014 Nov. PMID 25176448
    2. Prevalence of variants in methylenetetrahydrofolate reductase and the severity of pulmonary vascular disease. Day RW, et al. Pediatr Cardiol, 2015 Mar. PMID 25304246
    3. Is there a role for the MTHFR 677C>T and 1298A>C polymorphisms in methotrexate-induced liver toxicity? te Loo DM, et al. Pharmacogenomics, 2014 Aug. PMID 25303291
    4. 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
    5. 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

    See all (1000) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Association between methylenetetrahydrofolate reductase C677T polymorphisms and male oligozoospermia, asthenozoospermia or oligoasthenozoospermia: a case-control study.
      Title: Association between methylenetetrahydrofolate reductase C677T polymorphisms and male oligozoospermia, asthenozoospermia or oligoasthenozoospermia: a case-control study.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    7. 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.
    8. 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.
    9. 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.
    10. 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.
    Submit: New GeneRIF Correction See all GeneRIFs (2609)

    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
    		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)

    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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    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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