MTHFR (5,10-Methylenetetrahydrofolate reductase)

2005-08-01   Raphael Saffroy , Antoinette Lemoine , Brigitte Debuire 

Service de Biochimie et Biologie moleculaire, Hopital Paul Brousse, Faculte de Medecine Paris Sud, 94 800 Villejuif, France

Identity

HGNC
LOCATION
1p36.22
IMAGE
Atlas Image
LEGEND
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics
LOCUSID
ALIAS
-
FUSION GENES

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.

Proteins

Atlas Image
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 name
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 name
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 name
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 name
Depression
Disease
Hyperhomocysteinemia and the 677TT genotype were significantly related to depression.

Bibliography

Pubmed IDLast YearTitleAuthors
87580471996Genetic analysis of thermolabile methylenetetrahydrofolate reductase as a risk factor for myocardial infarction.Adams M et al
127962252003Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study.Bjelland I et al
157350512005One-carbon metabolism, MTHFR polymorphisms, and risk of breast cancer.Chen J et al
119299662002A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status.Friso S et al
76477791995A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.Frosst P et al
96803861998Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR)Goyette P et al
126491842003A common variant of the methylenetetrahydrofolate reductase gene (1p36) is associated with an increased risk of cancer.Heijmans BT et al
19983391991Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease.Kang SS et al
156884082005Methylenetetrahydrofolate reductase polymorphisms and risk of squamous cell carcinoma of the head and neck: a case-control analysis.Neumann AS et al
1267267620035,10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk: a HuGE minireview.Robien K et al
16273521992Methylenetetrahydrofolate reductase (MR) deficiency: thermolability of residual MR activity, methionine synthase activity, and methylcobalamin levels in cultured fibroblasts.Rosenblatt DS et al
150339052004The MTHFR 677C > T polymorphism is associated with an increased risk of hepatocellular carcinoma in patients with alcoholic cirrhosis.Saffroy R et al
120839672001Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical consequences.Schwahn B et al
149776392004Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review.Sharp L et al
128837042003Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms in patients with small cell and non-small cell lung cancer.Siemianowicz K et al
105360041999Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults.Skibola CF et al
146522852003Esophageal and gastric cardia cancer risk and folate- and vitamin B(12)-related polymorphisms in Linxian, China.Stolzenberg-Solomon RZ et al
123707782002Multiple transcription start sites and alternative splicing in the methylenetetrahydrofolate reductase gene result in two enzyme isoforms.Tran P et al
112744242001Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia.Wiemels JL et al

Other Information

Locus ID:

NCBI: 4524
MIM: 607093
HGNC: 7436
Ensembl: ENSG00000177000

Variants:

dbSNP: 4524
ClinVar: 4524
TCGA: ENSG00000177000
COSMIC: MTHFR

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000177000ENST00000376486F8W9T8
ENSG00000177000ENST00000376583P42898
ENSG00000177000ENST00000376585P42898
ENSG00000177000ENST00000376590P42898
ENSG00000177000ENST00000376592P42898
ENSG00000177000ENST00000413656A0A1B0GXD9
ENSG00000177000ENST00000418034Q5SNW5
ENSG00000177000ENST00000423400Q5SNW7
ENSG00000177000ENST00000641407A0A286YFD0
ENSG00000177000ENST00000641446A0A286YF17
ENSG00000177000ENST00000641747A0A286YF47
ENSG00000177000ENST00000641820L7P8G6

Expression (GTEx)

0
5
10
15
20
25
30

Pathways

PathwaySourceExternal ID
One carbon pool by folateKEGGko00670
One carbon pool by folateKEGGhsa00670
Metabolic pathwaysKEGGhsa01100
Carbon metabolismKEGGhsa01200
Carbon metabolismKEGGko01200
MetabolismREACTOMER-HSA-1430728
Metabolism of vitamins and cofactorsREACTOMER-HSA-196854
Metabolism of water-soluble vitamins and cofactorsREACTOMER-HSA-196849
Metabolism of folate and pterinesREACTOMER-HSA-196757
Antifolate resistanceKEGGko01523
Antifolate resistanceKEGGhsa01523

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA10505vitamin b-complex, plainChemicalClinicalAnnotationassociatedPD22926161
PA10810pemetrexedChemicalClinicalAnnotationassociatedPD19307503, 20634689, 24732178, 29662106
PA128406954Weight gainDiseaseMultilinkAnnotationassociated24279860
PA128406956fluorouracilChemicalClinicalAnnotation, VipGeneassociatedPD12083967, 17700593, 18245544, 18299612, 19384296, 20385995, 20638924, 20819423, 23314736, 23407049, 23736036, 24167597, 24980946, 25331073, 26014925, 26967565, 27557140, 27738344, 27864592, 27995989, 29134491, 29845393
PA130232992bevacizumabChemicalClinicalAnnotationassociatedPD19307503, 20634689, 29662106
PA131285527oxaliplatinChemicalClinicalAnnotationassociatedPD17700593, 18245544, 20385995, 20819423, 23407049, 24980946, 25331073, 27557140, 27864592, 29134491, 29845393
PA150516584HomocysteinemiaDiseaseVipGeneassociated12083967
PA164713398Vitamin B-complex, Incl. CombinationsChemicalClinicalAnnotationassociatedPD27035272, 27520898, 31058543
PA166123368schizoaffective disorderDiseaseClinicalAnnotationassociatedPD24725652
PA166153643rs1801131VariantGuidelineAnnotation, VipGeneassociated15608557, 16187112, 12083967
PA166153644rs1801133VariantGuidelineAnnotation, VipGeneassociated12083967, 12738713, 14647408, 15781665, 16187112, 16522920, 16672082, 16777985, 7647779, 11710708
PA166154581rs4149081VariantGuidelineAnnotationassociated
PA166154633rs11045879VariantGuidelineAnnotationassociated
PA166182939l-methylfolateChemicalClinicalAnnotationassociatedPD27035272, 27520898, 31058543
PA443228Abortion, HabitualDiseaseVipGeneassociated12083967
PA443319Alzheimer DiseaseDiseaseVipGeneassociated12083967
PA443425ArteriosclerosisDiseaseVipGeneassociated
PA443433Arthritis, Juvenile RheumatoidDiseaseClinicalAnnotation, VariantAnnotationambiguousPD16572443, 18322994, 18381794, 19193698, 19827168, 20386493, 20472929, 20514079, 20595278, 20863444, 21931346, 23095111, 24624914, 27217051
PA443434Arthritis, RheumatoidDiseaseClinicalAnnotation, VariantAnnotation, VipGeneambiguousPD12083967, 16439441, 16572443, 18322994, 18381794, 19193698, 19827168, 19858780, 20386493, 20472929, 20514079, 20595278, 20863444, 21931346, 23095111, 24624914, 25084201, 25618758, 26616421, 27217051
PA443560Breast NeoplasmsDiseaseVipGeneassociated12083967
PA443580Burkitt LymphomaDiseaseClinicalAnnotationassociatedPKPD15781665, 16013960, 16501586, 17323057, 17488658, 17512587, 18368069, 18987660, 21747412, 23089671, 23488607, 24241962, 25065700, 25303299, 28696419, 29683944
PA443622Carcinoma, Non-Small-Cell LungDiseaseClinicalAnnotationassociatedPD19307503, 24732178
PA443635Cardiovascular DiseasesDiseaseVipGeneassociated12083967
PA443685Uterine Cervical NeoplasmsDiseaseVipGeneassociated12083967
PA443736Cleft LipDiseaseVipGeneassociated12083967
PA443737Cleft PalateDiseaseVipGeneassociated12083967
PA443756Colonic NeoplasmsDiseaseClinicalAnnotationassociatedPD24980946, 29134491
PA443796Coronary Artery DiseaseDiseaseClinicalAnnotationassociatedPD18622257
PA443933Down SyndromeDiseaseVipGeneassociated12083967
PA443937Drug ToxicityDiseaseClinicalAnnotation, VariantAnnotationambiguousPD12915598, 16572443, 17323057, 18322994, 18381794, 19193698, 19827168, 20386493, 20472929, 20514079, 20595278, 20863444, 21931346, 23095111, 24624914, 27217051
PA444065EpilepsyDiseaseClinicalAnnotationassociatedPD
PA444320Graft vs Host DiseaseDiseaseClinicalAnnotationassociatedPD16920564, 19005482
PA444552HypertensionDiseaseClinicalAnnotationassociatedPD15226090, 16081343
PA444750LeukemiaDiseaseClinicalAnnotation, VariantAnnotation, VipGeneambiguousPD12083967, 12915598, 16920564, 19005482
PA444818Lung NeoplasmsDiseaseVipGeneassociated12083967
PA444845Lymphoma, Non-HodgkinDiseaseClinicalAnnotationassociatedPKPD15781665, 16013960, 16501586, 17323057, 17488658, 17512587, 18368069, 18987660, 21747412, 23089671, 23488607, 24241962, 25065700, 25303299, 28696419, 29683944
PA444937MesotheliomaDiseaseClinicalAnnotationassociatedPD19307503, 24732178
PA445019Myocardial InfarctionDiseaseClinicalAnnotationassociatedPD18622257
PA445062NeoplasmsDiseaseClinicalAnnotation, VipGeneassociatedPKPD11418485, 12083967, 12453860, 12915598, 14647408, 15051775, 15781665, 16013960, 16019535, 16462575, 16463153, 16501586, 16870553, 17180579, 17323057, 17488658, 17512587, 17700593, 18245544, 18299612, 18458567, 18987660, 19159907, 19307503, 19384296, 20385995, 20634689, 20638924, 20819423, 21605004, 21644011, 21747412, 22143415, 22838948, 23089671, 23314736, 23407049, 23488607, 23648444, 23736036, 24167597, 24241962, 24637499, 25007187, 25065700, 25110820, 25303299, 25331073, 25778468, 26014925, 26967565, 27399166, 27557140, 27738344, 27864592, 27995989, 28696419, 29134491, 29662106, 29683944, 29845393
PA445095Neural Tube DefectsDiseaseVipGeneassociated16672082, 12083967
PA445204Ovarian NeoplasmsDiseaseVipGeneassociated12083967
PA445398Pre-EclampsiaDiseaseVipGeneassociated12083967
PA445403Pregnancy ComplicationsDiseaseVipGeneassociated12083967
PA446108Colorectal NeoplasmsDiseaseMultilinkAnnotation, VipGeneassociated12083967, 25823789
PA446155Precursor Cell Lymphoblastic Leukemia-LymphomaDiseaseClinicalAnnotation, VariantAnnotationambiguousPKPD14647408, 15569990, 15781665, 16013960, 16019535, 16501586, 17323057, 17488658, 17512587, 18368069, 18458567, 18987660, 21747412, 22838948, 23089671, 23488607, 23652803, 24241962, 25065700, 25303299, 28696419, 29683944
PA446171Leukemia, Myelogenous, Chronic, BCR-ABL PositiveDiseaseClinicalAnnotationassociatedPD16920564, 19005482
PA446198Arthritis, PsoriaticDiseaseClinicalAnnotationassociatedPD16572443, 18322994, 18381794, 19193698, 19827168, 20386493, 20472929, 20514079, 20595278, 20863444, 21931346, 23095111, 24624914, 27217051
PA446286Spina Bifida CysticaDiseaseVipGeneassociated16672082
PA446309Lymphoma, T-CellDiseaseClinicalAnnotationassociatedPKPD15781665, 16013960, 16501586, 17323057, 17488658, 17512587, 18368069, 18987660, 21747412, 23089671, 23488607, 24241962, 25065700, 25303299, 28696419, 29683944
PA446411Endometrial NeoplasmsDiseaseVipGeneassociated12083967
PA446878Cocaine-Related DisordersDiseaseClinicalAnnotationassociatedPD23335901
PA446892HyperhomocysteinemiaDiseaseVipGeneassociated12083967
PA447215Psychotic DisordersDiseaseClinicalAnnotationassociatedPD
PA447216SchizophreniaDiseaseClinicalAnnotation, VipGeneassociatedPD12083967, 17976958, 24725652
PA447278DepressionDiseaseVipGeneassociated12083967
PA447298venous thromboembolismDiseaseVipGeneassociated12083967
PA447321Depressive Disorder, MajorDiseaseClinicalAnnotationassociatedPD27035272, 27520898, 31058543
PA448561benazeprilChemicalClinicalAnnotationassociatedPD15226090, 16081343
PA448771capecitabineChemicalClinicalAnnotationassociatedPD17700593, 18245544, 18299612, 19384296, 20385995, 20638924, 20819423, 23314736, 23407049, 23736036, 24167597, 25331073, 26014925, 26967565, 27557140, 27738344, 27864592, 27995989, 29134491, 29845393
PA448785carbamazepineChemicalVipGeneassociated12083967
PA448794carbidopaChemicalVipGeneassociated12083967
PA448803carboplatinChemicalClinicalAnnotationassociatedPD19159907, 19307503, 20634689, 21605004, 27995989, 29662106
PA449014cisplatinChemicalClinicalAnnotationassociatedPD19159907, 19307503, 20634689, 21605004, 27995989, 29662106
PA449061clozapineChemicalClinicalAnnotationassociatedPD24725652
PA449376disulfiramChemicalClinicalAnnotationassociatedPD23335901
PA449692folic acidChemicalClinicalAnnotation, VipGeneassociatedPKPD16672082, 19307503, 20634689, 22926161, 29317847, 29662106
PA450198leucovorinChemicalClinicalAnnotationassociatedPD17700593, 18245544, 20385995, 20819423, 23407049, 24980946, 25331073, 27557140, 27864592, 29134491, 29845393
PA450213levodopaChemicalVipGeneassociated12083967
PA450379mercaptopurineChemicalClinicalAnnotation, VariantAnnotationambiguousPD17323057, 18458567, 22838948
PA450428methotrexateChemicalClinicalAnnotation, GuidelineAnnotation, VariantAnnotation, VipGeneambiguousPKPD11418485, 12083967, 12453860, 12915598, 14647408, 15051775, 15569990, 15781665, 15797993, 16013960, 16019535, 16439441, 16462575, 16463153, 16501586, 16572443, 16870553, 16920564, 17180579, 17323057, 17488658, 17512587, 18322994, 18368069, 18381794, 18458567, 18987660, 19005482, 19159907, 19193698, 19827168, 19858780, 20386493, 20472929, 20514079, 20595278, 20863444, 21644011, 21747412, 21931346, 22143415, 22838948, 23089671, 23095111, 23488607, 23648444, 23652803, 24241962, 24624914, 24637499, 25007187, 25065700, 25084201, 25110820, 25303299, 25618758, 25778468, 26014925, 26616421, 27217051, 27399166, 28696419, 29683944
PA450645nitrous oxideChemicalClinicalAnnotationassociatedPD18580170
PA450688olanzapineChemicalClinicalAnnotationassociatedPD24725652
PA450911phenobarbitalChemicalClinicalAnnotationassociatedPD
PA450947phenytoinChemicalClinicalAnnotation, VipGeneassociatedPD12083967
PA451089pravastatinChemicalClinicalAnnotationassociatedPD18622257
PA451547sulfasalazineChemicalVipGeneassociated12083967
PA451846valproic acidChemicalVipGeneassociated12083967
PA451892cyanocobalaminChemicalClinicalAnnotationassociatedPD19307503, 20634689, 29662106
PA452233antipsychoticsChemicalClinicalAnnotationassociatedPD17976958

References

Pubmed IDYearTitleCitations
171927852007Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database.609
194304832009Genome-wide association study identifies eight loci associated with blood pressure.476
185839792008Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database.395
119299662002A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status.223
119299662002A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status.223
1079155920005,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review.184
123876552002MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis.148
169179392006Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism.138
205347412010Association of CR1, CLU and PICALM with Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals.108
203517142011Poor replication of candidate genes for major depressive disorder using genome-wide association data.92

Citation

Raphael Saffroy ; Antoinette Lemoine ; Brigitte Debuire

MTHFR (5,10-Methylenetetrahydrofolate reductase)

Atlas Genet Cytogenet Oncol Haematol. 2005-08-01

Online version: http://atlasgeneticsoncology.org/gene/41448/mthfr-(5-10-methylenetetrahydrofolate-reductase)