MTHFR (5,10-Methylenetetrahydrofolate reductase)

Identity

Other names	MTR
	MTHR
HGNC	MTHFR
Location	1p36.22

DNA/RNA

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.

Protein

	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

Mutations

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

	Nomenclature
HGNC	MTHFR   7436
Entrez_Gene	MTHFR  4524  5,10-methylenetetrahydrofolate reductase (NADPH)
	Cards
Atlas	MTHFRID41448ch1p36
GeneCards	MTHFR
Ensembl	MTHFR [Search_View]   ENSG00000177000 [Gene_View]
Genatlas	MTHFR
GeneLynx	MTHFR
eGenome	MTHFR
euGene	4524
	Genomic and cartography
GoldenPath	MTHFR  -  1p36.22   chr1:11768374-11788702 -  1p36.3   [Description]    (hg18-Mar_2006)
Ensembl	MTHFR - 1p36.3 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	MTHFR
	Gene and transcription
Genbank	AB209113 [ ENTREZ ]
Genbank	AJ237672 [ ENTREZ ]
Genbank	AK312907 [ ENTREZ ]
Genbank	AY046560 [ ENTREZ ]
Genbank	AY046561 [ ENTREZ ]
RefSeq	NM_005957 [ SRS ]    NM_005957 [ ENTREZ ]
RefSeq	AC_000044 [ SRS ]    AC_000044 [ ENTREZ ]
RefSeq	AC_000133 [ SRS ]    AC_000133 [ ENTREZ ]
RefSeq	NC_000001 [ SRS ]    NC_000001 [ ENTREZ ]
RefSeq	NT_021937 [ SRS ]    NT_021937 [ ENTREZ ]
RefSeq	NW_001838534 [ SRS ]    NW_001838534 [ ENTREZ ]
RefSeq	NW_923572 [ SRS ]    NW_923572 [ ENTREZ ]
AceView	MTHFR AceView - NCBI
Unigene	Hs.214142 [ SRS ]    Hs.214142 [ NCBI ]     HS214142 [ spliceNest ]
Fast-db	5611 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	P42898 [ SRS]    P42898 [ EXPASY ]     P42898 [ INTERPRO ]     P42898 [ UNIPROT ]
Interpro	IPR004621 Fadh2_euk [ SRS ]    IPR004621 Fadh2_euk [ EBI ]
Interpro	IPR003171 Mehydrof_redctse [ SRS ]    IPR003171 Mehydrof_redctse [ EBI ]
CluSTr	P42898
Pfam	PF02219 MTHFR [ SRS ]    PF02219 MTHFR [ Sanger ]    pfam02219 [ NCBI-CDD ]
Blocks	P42898
HPRD	06158
	Protein Interaction databases
DIP	P42898
IntAct	P42898
	Polymorphism : SNP, mutations, diseases
OMIM	236250;607093    [ map ]
GENECLINICS	236250;607093
SNP	MTHFR [dbSNP-NCBI]
SNP	NM_005957 [SNP-NCI]
SNP	MTHFR [GeneSNPs - Utah]  MTHFR] [HGBASE - SRS]
HAPMAP	MTHFR [HAPMAP]
HGMD	MTHFR
	General knowledge
Family Browser	MTHFR [UCSC Family Browser]
SOURCE	NM_005957
SMD	Hs.214142
SAGE	Hs.214142
GO	methylenetetrahydrofolate reductase (NADPH) activity [Amigo]  methylenetetrahydrofolate reductase (NADPH) activity
GO	methylenetetrahydrofolate reductase (NADPH) activity [Amigo]  methylenetetrahydrofolate reductase (NADPH) activity
GO	methylenetetrahydrofolate reductase (NADPH) activity [Amigo]  methylenetetrahydrofolate reductase (NADPH) activity
GO	protein binding [Amigo]  protein binding
GO	cytosol [Amigo]  cytosol
GO	amino acid metabolic process [Amigo]  amino acid metabolic process
GO	methionine metabolic process [Amigo]  methionine metabolic process
GO	blood circulation [Amigo]  blood circulation
GO	methionine biosynthetic process [Amigo]  methionine biosynthetic process
GO	oxidoreductase activity [Amigo]  oxidoreductase activity
GO	oxidation reduction [Amigo]  oxidation reduction
KEGG	One carbon pool by folate
KEGG	Methane metabolism
PubGene	MTHFR
TreeFam	MTHFR
CTD	4524 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	MTHFR Related clones (RZPD - Berlin)
	PubMed
PubMed	499 Pubmed reference(s) in LocusLink

Bibliography

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

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Contributor(s)

Written	08-2005	Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire

Citation

This paper should be referenced as such :

Saffroy R, Lemoine A, Debuire B . MTHFR (5,10-Methylenetetrahydrofolate reductase). Atlas Genet Cytogenet Oncol Haematol. August 2005 . URL : http://AtlasGeneticsOncology.org/Genes/MTHFRID41448ch1p36.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Mon Aug 11 21:15:36 2008