Human Gene MTHFR (ENST00000376590.8) Description and Page Index
  Description: Homo sapiens methylenetetrahydrofolate reductase (MTHFR), transcript variant 2, mRNA. (from RefSeq NM_005957)
RefSeq Summary (NM_005957): 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].
Gencode Transcript: ENST00000376590.8
Gencode Gene: ENSG00000177000.12
Transcript (Including UTRs)
   Position: hg38 chr1:11,786,603-11,806,920 Size: 20,318 Total Exon Count: 12 Strand: -
Coding Region
   Position: hg38 chr1:11,790,680-11,803,116 Size: 12,437 Coding Exon Count: 11 

Page IndexSequence and LinksUniProtKB CommentsMalaCardsCTDRNA-Seq Expression
Microarray ExpressionRNA StructureProtein StructureOther SpeciesGO AnnotationsmRNA Descriptions
PathwaysOther NamesMethods
Data last updated: 2019-09-04

-  Sequence and Links to Tools and Databases
 
Genomic Sequence (chr1:11,786,603-11,806,920)mRNA (may differ from genome)Protein (656 aa)
Gene SorterGenome BrowserOther Species FASTAVisiGeneGene interactionsTable Schema
BioGPSCGAPEnsemblEntrez GeneExonPrimerGeneCards
HGNCHPRDLynxMGImyGene2neXtProt
OMIMPubMedReactomeStanford SOURCEUniProtKBWikipedia

-  Comments and Description Text from UniProtKB
  ID: MTHR_HUMAN
DESCRIPTION: RecName: Full=Methylenetetrahydrofolate reductase; EC=1.5.1.20;
FUNCTION: Catalyzes the conversion of 5,10- methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co- substrate for homocysteine remethylation to methionine.
CATALYTIC ACTIVITY: 5-methyltetrahydrofolate + NAD(P)(+) = 5,10- methylenetetrahydrofolate + NAD(P)H.
COFACTOR: FAD.
ENZYME REGULATION: Allosterically regulated by S- adenosylmethionine.
PATHWAY: One-carbon metabolism; tetrahydrofolate interconversion.
SUBUNIT: Homodimer.
POLYMORPHISM: Genetic variation in MTHFR influences susceptibility to occlusive vascular disease, neural tube defects (NTD), colon cancer and acute leukemia.
DISEASE: Defects in MTHFR are the cause of methylenetetrahydrofolate reductase deficiency (MTHFRD) [MIM:236250]. MTHFRD is autosomal recessive disorder with a wide range of features including homocysteinuria, homocysteinemia [MIM:603174], developmental delay, severe mental retardation, perinatal death, psychiatric disturbances, and later-onset neurodegenerative disorders.
DISEASE: Defects in MTHFR may be a cause of susceptibility to ischemic stroke (ISCHSTR) [MIM:601367]; also known as cerebrovascular accident or cerebral infarction. A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors.
DISEASE: Defects in MTHFR may be a cause of susceptibility to folate-sensitive neural tube defects (FS-NTD) [MIM:601634]. The most common NTDs are open spina bifida (myelomeningocele) and anencephaly.
SIMILARITY: Belongs to the methylenetetrahydrofolate reductase family.
WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/MTHFRID41448ch1p36.html";
WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MTHFR";
WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/mthfr/";
WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and polymorphism database; URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=MTHFR";
WEB RESOURCE: Name=Wikipedia; Note=Methylenetetrahydrofolate reductase entry; URL="http://en.wikipedia.org/wiki/Methylenetetrahydrofolate_reductase";

-  MalaCards Disease Associations
  MalaCards Gene Search: MTHFR
Diseases sorted by gene-association score: homocystinuria due to mthfr deficiency* (1671), thrombophilia due to thrombin defect* (578), neural tube defects, folate-sensitive* (343), schizophrenia* (284), mthfr thermolabile variant* (143), mthfr-related altered drug metabolism* (100), vascular disease (66), anencephaly* (44), homocysteinemia (39), myelomeningocele (38), acute leukemia (33), placental abruption (32), neural tube defects (30), placenta disease (24), spina bifida occulta (23), retinal vein occlusion (23), branch retinal artery occlusion (23), lemierre's syndrome (22), cerebral atherosclerosis (21), central retinal vein occlusion (21), hyperhomocysteinemia (20), amino acid metabolic disorder (19), vitamin b12 deficiency (19), nonarteritic anterior ischemic optic neuropathy (19), mthfr gene mutation (19), spinal cord infarction (18), post-traumatic epilepsy (18), methotrexate toxicity or dose selection* (18), colorectal adenoma (17), retinal artery occlusion (17), vein disease (16), arteritic anterior ischemic optic neuropathy (16), lateral sinus thrombosis (16), cerebrovascular disease (15), thrombophilia due to antithrombin iii deficiency (14), homocystinuria (14), sudden sensorineural hearing loss (13), protein s deficiency (13), inferior vena cava interruption (13), ischemic optic neuropathy (13), eclampsia (13), budd-chiari syndrome (13), hemifacial spasm (13), pediatric osteosarcoma (13), stomach cancer (13), riboflavin deficiency (13), upper thoracic spina bifida cystica* (12), cervicothoracic spina bifida cystica* (12), cervical spina bifida cystica* (12), lumbosacral spina bifida cystica* (12), thoracolumbosacral spina bifida cystica* (12), total spina bifida cystica* (12), upper thoracic spina bifida aperta* (12), thoracolumbosacral spina bifida aperta* (12), lumbosacral spina bifida aperta* (12), cervical spina bifida aperta* (12), cervicothoracic spina bifida aperta* (12), total spina bifida aperta* (12), encephalomalacia (12), porencephaly (12), protein c deficiency (12), thrombophilia (12), gastric cardia adenocarcinoma (11), portal vein thrombosis (11), lens subluxation (11), thrombophlebitis (11), antiphospholipid syndrome (11), cleft lip +/- cleft palate (10), hellp syndrome (10), migraine with aura (10), pulmonary embolism (10), neonatal stroke (10), retinal vascular disease (10), gastric cancer, somatic (9), childhood leukemia (9), livedoid vasculopathy (9), amaurosis fugax (9), catastrophic antiphospholipid syndrome (9), acute lymphoblastic leukemia, childhood (9), pyruvate kinase deficiency (9), nutritional deficiency disease (9), intracranial thrombosis (9), osteonecrosis (8), stroke, ischemic (8), osteoporotic fracture (8), cervical intraepithelial neoplasia (8), intracranial hypertension (8), vascular dementia (8), migraine with or without aura 1 (8), pregnancy loss, recurrent 1 (8), thrombophilia due to activated protein c resistance (8), exfoliation syndrome (8), blood protein disease (8), cleft lip (8), buerger disease (7), cleft palate, isolated (7), mucositis (7), glycine n-methyltransferase deficiency (7), patent foramen ovale (7), acute lymphocytic leukemia (7), carotid stenosis (7), retinal vascular occlusion (7), gastroschisis (7), thrombosis (7), schizencephaly (7), pre-eclampsia (7), cerebral palsy (7), primary angle-closure glaucoma (6), vitamin metabolic disorder (6), mesenteric vascular occlusion (6), hematopoietic stem cell transplantation (6), nephrosclerosis (6), methylmalonic acidemia (6), mastoiditis (6), gastrointestinal stromal tumor (6), intestinal benign neoplasm (6), sickle cell anemia (6), hemoglobin c disease (5), coronary artery disease (5), carotid artery dissection (5), gastric cardia carcinoma (5), moyamoya disease (5), thrombasthenia (5), gastrointestinal system benign neoplasm (5), omphalocele (5), inherited metabolic disorder (5), megaloblastic anemia (5), ischemic heart disease (5), testicular infarct (5), preeclampsia/eclampsia 1 (5), hereditary colorectal cancer (4), blood coagulation disease (4), holocarboxylase synthetase deficiency (4), ariboflavinosis (4), marantic endocarditis (4), hepatic vascular disease (4), hepatic infarction (4), uterine disease (4), bipolar disorder (4), heart disease (4), transcobalamin ii deficiency (4), down syndrome (3), myocardial infarction (3), colorectal cancer (3), differentiated thyroid carcinoma (3), artery disease (3), tetralogy of fallot (2), cleft lip/palate (2), autism spectrum disorder (1), physical disorder (1)
* = Manually curated disease association

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 7.34 RPKM in Ovary
Total median expression: 162.90 RPKM



View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
 
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -409.001046-0.391 Picture PostScript Text
3' UTR -1756.504077-0.431 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR004621 - Fadh2_euk
IPR003171 - Mehydrof_redctse

Pfam Domains:
PF02219 - Methylenetetrahydrofolate reductase

ModBase Predicted Comparative 3D Structure on P42898
FrontTopSide
The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.

-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
Genome BrowserGenome BrowserNo orthologNo orthologGenome BrowserNo ortholog
Gene Details     
Gene Sorter     
MGIRGD  WormBase 
Protein SequenceProtein Sequence  Protein Sequence 
AlignmentAlignment  Alignment 

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0003824 catalytic activity
GO:0004489 methylenetetrahydrofolate reductase (NAD(P)H) activity
GO:0016491 oxidoreductase activity
GO:0044877 macromolecular complex binding
GO:0050660 flavin adenine dinucleotide binding
GO:0050661 NADP binding
GO:0072341 modified amino acid binding

Biological Process:
GO:0001666 response to hypoxia
GO:0006520 cellular amino acid metabolic process
GO:0006555 methionine metabolic process
GO:0008015 blood circulation
GO:0008152 metabolic process
GO:0031060 regulation of histone methylation
GO:0033274 response to vitamin B2
GO:0035999 tetrahydrofolate interconversion
GO:0042493 response to drug
GO:0043200 response to amino acid
GO:0046500 S-adenosylmethionine metabolic process
GO:0046653 tetrahydrofolate metabolic process
GO:0046655 folic acid metabolic process
GO:0050667 homocysteine metabolic process
GO:0051593 response to folic acid
GO:0055114 oxidation-reduction process
GO:0070555 response to interleukin-1
GO:0070829 heterochromatin maintenance

Cellular Component:
GO:0005829 cytosol
GO:0045202 synapse


-  Descriptions from all associated GenBank mRNAs
  LF206719 - JP 2014500723-A/14222: Polycomb-Associated Non-Coding RNAs.
MA442296 - JP 2018138019-A/14222: Polycomb-Associated Non-Coding RNAs.
LF213889 - JP 2014500723-A/21392: Polycomb-Associated Non-Coding RNAs.
MA449466 - JP 2018138019-A/21392: Polycomb-Associated Non-Coding RNAs.
AB209113 - Homo sapiens mRNA for 5,10-methylenetetrahydrofolate reductase (NADPH) variant protein.
BC053509 - Homo sapiens 5,10-methylenetetrahydrofolate reductase (NADPH), mRNA (cDNA clone MGC:59799 IMAGE:6374885), complete cds.
AJ237672 - Homo sapiens mRNA for methylenetetrahydrofolate reductase.
JQ429447 - Homo sapiens 5,10-methylenetetrahydrofolate reductase isoform 2 (MTHFR) mRNA, complete cds, alternatively spliced.
AK312907 - Homo sapiens cDNA, FLJ93354, highly similar to Homo sapiens 5,10-methylenetetrahydrofolate reductase (NADPH)(MTHFR), mRNA.
BC011614 - Homo sapiens 5,10-methylenetetrahydrofolate reductase (NADPH), mRNA (cDNA clone IMAGE:3949285), partial cds.
BC018766 - Homo sapiens 5,10-methylenetetrahydrofolate reductase (NADPH), mRNA (cDNA clone IMAGE:4299889).
DQ594849 - Homo sapiens piRNA piR-60961, complete sequence.
JD507239 - Sequence 488263 from Patent EP1572962.
JD531226 - Sequence 512250 from Patent EP1572962.
JD150319 - Sequence 131343 from Patent EP1572962.
LF357350 - JP 2014500723-A/164853: Polycomb-Associated Non-Coding RNAs.
MA592927 - JP 2018138019-A/164853: Polycomb-Associated Non-Coding RNAs.
LF357348 - JP 2014500723-A/164851: Polycomb-Associated Non-Coding RNAs.
MA592925 - JP 2018138019-A/164851: Polycomb-Associated Non-Coding RNAs.
LF357347 - JP 2014500723-A/164850: Polycomb-Associated Non-Coding RNAs.
MA592924 - JP 2018138019-A/164850: Polycomb-Associated Non-Coding RNAs.
LF357342 - JP 2014500723-A/164845: Polycomb-Associated Non-Coding RNAs.
MA592919 - JP 2018138019-A/164845: Polycomb-Associated Non-Coding RNAs.
AY046565 - Homo sapiens methylenetetrahydrofolate reductase short isoform mRNA, partial cds; alternatively spliced.
AY046561 - Homo sapiens methylenetetrahydrofolate reductase short isoform mRNA, partial cds; alternatively spliced.
AY046562 - Homo sapiens methylenetetrahydrofolate reductase long isoform mRNA, partial cds; alternatively spliced.
AY046563 - Homo sapiens methylenetetrahydrofolate reductase short isoform mRNA, partial cds; alternatively spliced.
AY046564 - Homo sapiens methylenetetrahydrofolate reductase short isoform mRNA, partial cds; alternatively spliced.
AY046560 - Homo sapiens methylenetetrahydrofolate reductase short isoform mRNA, partial cds; alternatively spliced.
JD442762 - Sequence 423786 from Patent EP1572962.

-  Biochemical and Signaling Pathways
  KEGG - Kyoto Encyclopedia of Genes and Genomes
hsa00670 - One carbon pool by folate
hsa00680 - Methane metabolism
hsa01100 - Metabolic pathways

BioCyc Knowledge Library
PWY-2201 - folate transformations I

Reactome (by CSHL, EBI, and GO)

Protein P42898 (Reactome details) participates in the following event(s):

R-HSA-200676 5,10-methyleneTHF polyglutamate + NADPH + H+ => 5-methylTHF polyglutamate + NADP+
R-HSA-196757 Metabolism of folate and pterines
R-HSA-196849 Metabolism of water-soluble vitamins and cofactors
R-HSA-196854 Metabolism of vitamins and cofactors
R-HSA-1430728 Metabolism

-  Other Names for This Gene
  Alternate Gene Symbols: B2R7A6, MTHR_HUMAN, NM_005957, P42898, Q5SNW9, Q7Z6M6, Q9UQR2, uc001atc.1, uc001atc.2, uc001atc.3, uc001atc.4
UCSC ID: uc001atc.4
RefSeq Accession: NM_005957
Protein: P42898 (aka MTHR_HUMAN)
CCDS: CCDS137.1

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.