Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

MTHFR (5,10-Methylenetetrahydrofolate reductase)


Other namesMTR
LocusID (NCBI) 4524
Location 1p36.22
Location_base_pair Starts at 11845787 and ends at 11866160 bp from pter ( according to hg19-Feb_2009)  [Mapping]
  Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics


Description The gene encompasses 19.3 kb of DNA; 11 exons
Transcription For MTHFR, transcripts of 9.0, 7.2, 6.3, 3.0 and 2.8 kb were observed. The different-sized transcripts result from alternate transcription start sites and multiple polyadenylation signals. The total abundance is low, and the proportion of each transcript differs among tissues.


  MTHFR metabolic pathway
Description 656 amino acids; 74.6 kDa protein.
Expression Expression is more intense in testis, intermediate in brain and kidney, and lower in other tissues.
Localisation Cytosolic
Function MTHFR catalyzes the conversion of 5,10- methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine.
Homology FAD-linked oxidoreductase


Germinal Two common polymorphisms 677C-T and 1298A-C have been identified. These polymorphisms are responsible for the synthesis of a thermolabile form of MTHFR. The 677TT genotype was particularly common in northern China (20%), southern Italy (26%), and Mexico (32%). The 677C>T mutation in the MTHFR gene is an important cause of mild hyperhomocysteinaemia. The second polymorphism at nucleotide position 1298, is not as well characterized.

Implicated in

Entity Homocystinuria due to deficiency of methylenetetrahydrofolate reductase activity
Disease This form of homocystinuria is caused by mutation in the 5,10-alpha-methylenetetrahydrofolate reductase gene. This homocystinuria is autosomal recessive and shows a wide range of clinical symptoms, such as developmental delay, severe mental retardation, perinatal death, psychiatric disturbances, and later-onset neurodegenerative disorders. In the classic form, both thermostable and thermolabile enzyme variants have been identified.
Entity Cancer
Disease In some cancers, folate and other nutrients involved in the MTHFR metabolic pathway appear to interact with MTHFR polymorphisms to further modify cancer risk. In most studies, MTHFR 677TT and 1298CC are associated with moderately reduced colorectal cancer risk, in particular in individuals who had higher folate levels. In individuals with low folate intake and/or high alcohol consumption, cancer risk may be increased. Morever, both adults and children with the variant forms of MTHFR seems to have a decreased risk of lymphoid leukemias. MTHFR polymorphisms were also associated with other cancers as breast, head and neck, liver, gastric or lung cancers.
Oncogenesis Reduction of 5,10-methylenetetrahydrofolate (methyleneTHF), a donor for methylating dUMP to dTMP in DNA synthesis, to 5-methyltetrahydrofolate (methylTHF), the primary methyl donor for methionine synthesis, is catalyzed by MTHFR. Diminution in the activity of the MTHFR enzyme increases the pool of methyleneTHF at the expense of the pool of methylTHF. Enhanced availability of methyleneTHF in the DNA synthesis pathway reduces misincorporation of uracil into DNA, which might otherwise result in double-strand breaks during uracil excision repair processes, thus increasing the risk of chromosomal aberrations. Morever, the MTHFR polymorphisms influences DNA methylation status through interaction with folate status.
Entity Coronary Artery Disease
Disease The 677TT MTHFR allele was correlated with coronary artery disease. However, the role of this polymorphism in the causation of coronary artery disease is controversial.
Entity Depression
Disease Hyperhomocysteinemia and the 677TT genotype were significantly related to depression.

To be noted

MTHFR polymorphisms influence the metabolism of folates and could modify the pharmacodynamics of antifolates and many other drugs whose metabolism, biochemical effects, or target structures require methylation reactions.

External links

HGNC (Hugo)MTHFR   7436
Entrez_Gene (NCBI)MTHFR  4524  methylenetetrahydrofolate reductase (NAD(P)H)
GeneCards (Weizmann)MTHFR
Ensembl (Hinxton)ENSG00000177000 [Gene_View]  chr1:11845787-11866160 [Contig_View]  MTHFR [Vega]
ICGC DataPortalENSG00000177000
Genatlas (Paris)MTHFR
SOURCE (Princeton)NM_005957
Genomic and cartography
GoldenPath (UCSC)MTHFR  -  1p36.22   chr1:11845787-11866160 -  1p36.3   [Description]    (hg19-Feb_2009)
EnsemblMTHFR - 1p36.3 [CytoView]
Mapping of homologs : NCBIMTHFR [Mapview]
OMIM119530   181500   188050   236250   601634   607093   
Gene and transcription
Genbank (Entrez)AB209113 AJ237672 AK312907 AY046560 AY046561
RefSeq transcript (Entrez)NM_005957
RefSeq genomic (Entrez)AC_000133 NC_000001 NC_018912 NG_013351 NT_021937 NW_001838534 NW_004929289
Consensus coding sequences : CCDS (NCBI)MTHFR
Cluster EST : UnigeneHs.737916 [ NCBI ]
CGAP (NCI)Hs.737916
Alternative Splicing : Fast-db (Paris)GSHG0001754
Alternative Splicing GalleryENSG00000177000
Gene ExpressionMTHFR [ NCBI-GEO ]     MTHFR [ SEEK ]   MTHFR [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP42898 (Uniprot)
NextProtP42898  [Medical]
With graphics : InterProP42898
Splice isoforms : SwissVarP42898 (Swissvar)
Domains : Interpro (EBI)Fadh2_euk [organisation]   Mehydrof_redctse [organisation]  
Related proteins : CluSTrP42898
Domain families : Pfam (Sanger)MTHFR (PF02219)   
Domain families : Pfam (NCBI)pfam02219   
DMDM Disease mutations4524
Blocks (Seattle)P42898
Human Protein AtlasENSG00000177000 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasP42898
IPIIPI00002487   IPI00930389   IPI00646654   IPI00646036   IPI00643819   IPI00642645   
Protein Interaction databases
IntAct (EBI)P42898
Interologous Interaction database P42898
Ontologies - Pathways
Ontology : AmiGOmethylenetetrahydrofolate reductase (NAD(P)H) activity  cytosol  cellular amino acid metabolic process  vitamin metabolic process  water-soluble vitamin metabolic process  blood circulation  methionine biosynthetic process  tetrahydrofolate interconversion  small molecule metabolic process  folic acid metabolic process  homocysteine metabolic process  modified amino acid binding  
Ontology : EGO-EBImethylenetetrahydrofolate reductase (NAD(P)H) activity  cytosol  cellular amino acid metabolic process  vitamin metabolic process  water-soluble vitamin metabolic process  blood circulation  methionine biosynthetic process  tetrahydrofolate interconversion  small molecule metabolic process  folic acid metabolic process  homocysteine metabolic process  modified amino acid binding  
Pathways : KEGGOne carbon pool by folate   
Protein Interaction DatabaseMTHFR
Wikipedia pathwaysMTHFR
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)MTHFR
snp3D : Map Gene to Disease4524
Genetic variants : HAPMAPMTHFR
Exome VariantMTHFR
ICGC programENSG00000177000 
Somatic Mutations in Cancer : COSMICMTHFR 
CONAN: Copy Number AnalysisMTHFR 
Mutations and Diseases : HGMDMTHFR
Genomic VariantsMTHFR  MTHFR [DGVbeta]
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
OMIM119530    181500    188050    236250    601634    607093   
Disease Genetic AssociationMTHFR
Huge Navigator MTHFR [HugePedia]  MTHFR [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneMTHFR
Homology/Alignments : Family Browser (UCSC)MTHFR
Phylogenetic Trees/Animal Genes : TreeFamMTHFR
Chemical/Protein Interactions : CTD4524
Chemical/Pharm GKB GenePA245
Clinical trialMTHFR
Cancer Resource (Charite)ENSG00000177000
Other databases
PubMed499 Pubmed reference(s) in Entrez


Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease.
Kang SS, Wong PW, Susmano A, Sora J, Norusis M, Ruggie N
American journal of human genetics. 1991 ; 48 (3) : 536-545.
PMID 1998339
Methylenetetrahydrofolate reductase (MR) deficiency: thermolability of residual MR activity, methionine synthase activity, and methylcobalamin levels in cultured fibroblasts.
Rosenblatt DS, Lue-Shing H, Arzoumanian A, Low-Nang L, Matiaszuk N
Biochemical medicine and metabolic biology. 1992 ; 47 (3) : 221-225.
PMID 1627352
A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.
Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP
Nature genetics. 1995 ; 10 (1) : 111-113.
PMID 7647779
Genetic analysis of thermolabile methylenetetrahydrofolate reductase as a risk factor for myocardial infarction.
Adams M, Smith PD, Martin D, Thompson JR, Lodwick D, Samani NJ
QJM : monthly journal of the Association of Physicians. 1996 ; 89 (6) : 437-444.
PMID 8758047
Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR)
Goyette P, Pai A, Milos R, Frosst P, Tran P, Chen Z, Chan M, Rozen R
Mammalian genome : official journal of the International Mammalian Genome Society. 1998 ; 9 (8) : 652-656.
PMID 9680386
Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults.
Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, Cartwright RA, Morgan G
Proceedings of the National Academy of Sciences of the United States of America. 1999 ; 96 (22) : 12810-12815.
PMID 10536004
Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical consequences.
Schwahn B, Rozen R
American journal of pharmacogenomics : genomics-related research in drug development and clinical practice. 2001 ; 1 (3) : 189-201.
PMID 12083967
Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia.
Wiemels JL, Smith RN, Taylor GM, Eden OB, Alexander FE, United Kingdom Childhood Cancer Study investigators, Greaves MF
Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (7) : 4004-4009.
PMID 11274424
A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status.
Friso S, Choi SW, Girelli D, Mason JB, Dolnikowski GG, Bagley PJ, Olivieri O, Jacques PF, Rosenberg IH, Corrocher R, Selhub J
Proceedings of the National Academy of Sciences of the United States of America. 2002 ; 99 (8) : 5606-5611.
PMID 11929966
Multiple transcription start sites and alternative splicing in the methylenetetrahydrofolate reductase gene result in two enzyme isoforms.
Tran P, Leclerc D, Chan M, Pai A, Hiou-Tim F, Wu Q, Goyette P, Artigas C, Milos R, Rozen R
Mammalian genome : official journal of the International Mammalian Genome Society. 2002 ; 13 (9) : 483-492.
PMID 12370778
Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study.
Bjelland I, Tell GS, Vollset SE, Refsum H, Ueland PM
Archives of general psychiatry. 2003 ; 60 (6) : 618-626.
PMID 12796225
A common variant of the methylenetetrahydrofolate reductase gene (1p36) is associated with an increased risk of cancer.
Heijmans BT, Boer JM, Suchiman HE, Cornelisse CJ, Westendorp RG, Kromhout D, Feskens EJ, Slagboom PE
Cancer research. 2003 ; 63 (6) : 1249-1253.
PMID 12649184
Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms in patients with small cell and non-small cell lung cancer.
Siemianowicz K, Gminski J, Garczorz W, Slabiak N, Goss M, Machalski M, Magiera-Molendowska H
Oncology reports. 2003 ; 10 (5) : 1341-1344.
PMID 12883704
5,10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk: a HuGE minireview.
Robien K, Ulrich CM
American journal of epidemiology. 2003 ; 157 (7) : 571-582.
PMID 12672676
Esophageal and gastric cardia cancer risk and folate- and vitamin B(12)-related polymorphisms in Linxian, China.
Stolzenberg-Solomon RZ, Qiao YL, Abnet CC, Ratnasinghe DL, Dawsey SM, Dong ZW, Taylor PR, Mark SD
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2003 ; 12 (11 Pt 1) : 1222-1226.
PMID 14652285
The MTHFR 677C > T polymorphism is associated with an increased risk of hepatocellular carcinoma in patients with alcoholic cirrhosis.
Saffroy R, Pham P, Chiappini F, Gross-Goupil M, Castera L, Azoulay D, Barrier A, Samuel D, Debuire B, Lemoine A
Carcinogenesis. 2004 ; 25 (8) : 1443-1448.
PMID 15033905
Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review.
Sharp L, Little J
American journal of epidemiology. 2004 ; 159 (5) : 423-443.
PMID 14977639
One-carbon metabolism, MTHFR polymorphisms, and risk of breast cancer.
Chen J, Gammon MD, Chan W, Palomeque C, Wetmur JG, Kabat GC, Teitelbaum SL, Britton JA, Terry MB, Neugut AI, Santella RM
Cancer research. 2005 ; 65 (4) : 1606-1614.
PMID 15735051
Methylenetetrahydrofolate reductase polymorphisms and risk of squamous cell carcinoma of the head and neck: a case-control analysis.
Neumann AS, Lyons HJ, Shen H, Liu Z, Shi Q, Sturgis EM, Shete S, Spitz MR, El-Naggar A, Hong WK, Wei Q
International journal of cancer. Journal international du cancer. 2005 ; 115 (1) : 131-136.
PMID 15688408
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI


Written08-2005Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire


This paper should be referenced as such :
Saffroy, R ; Lemoine, A ; Debuire, B
MTHFR (5,10-Methylenetetrahydrofolate reductase)
Atlas Genet Cytogenet Oncol Haematol. 2005;9(4):310-312.
Free online version   Free pdf version   [Bibliographic record ]

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Fri Jul 11 17:20:26 CEST 2014

Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us