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P42898 (MTHR_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 141. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Methylenetetrahydrofolate reductase

EC=1.5.1.20
Gene names
Name:MTHFR
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length656 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

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 structure

Homodimer.

Polymorphism

Genetic variation in MTHFR influences susceptibility to occlusive vascular disease, neural tube defects (NTD), colon cancer and acute leukemia.

Involvement in disease

Methylenetetrahydrofolate reductase deficiency (MTHFRD) [MIM:236250]: 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.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.13 Ref.17 Ref.21 Ref.25

Ischemic stroke (ISCHSTR) [MIM:601367]: 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.
Note: Disease susceptibility is associated with variations affecting the gene represented in this entry. Ref.26

Folate-sensitive neural tube defects (FS-NTD) [MIM:601634]: The most common NTDs are open spina bifida (myelomeningocele) and anencephaly.
Note: Disease susceptibility is associated with variations affecting the gene represented in this entry. Ref.14 Ref.16 Ref.23

Sequence similarities

Belongs to the methylenetetrahydrofolate reductase family.

Ontologies

Keywords
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDisease mutation
   LigandFAD
Flavoprotein
NADP
   Molecular functionOxidoreductase
   Technical termAllosteric enzyme
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processS-adenosylmethionine metabolic process

Inferred from electronic annotation. Source: Ensembl

blood circulation

Traceable author statement Ref.15. Source: ProtInc

cellular amino acid metabolic process

Traceable author statement Ref.15. Source: ProtInc

folic acid metabolic process

Traceable author statement. Source: Reactome

homocysteine metabolic process

Inferred from direct assay PubMed 20031578. Source: UniProtKB

methionine biosynthetic process

Inferred from electronic annotation. Source: Ensembl

response to drug

Inferred from electronic annotation. Source: Ensembl

response to folic acid

Inferred from electronic annotation. Source: Ensembl

response to hypoxia

Inferred from electronic annotation. Source: Ensembl

response to interleukin-1

Inferred from electronic annotation. Source: Ensembl

response to vitamin B2

Inferred from electronic annotation. Source: Ensembl

small molecule metabolic process

Traceable author statement. Source: Reactome

tetrahydrofolate interconversion

Inferred from electronic annotation. Source: UniProtKB-UniPathway

vitamin metabolic process

Traceable author statement. Source: Reactome

water-soluble vitamin metabolic process

Traceable author statement. Source: Reactome

   Cellular_componentcytosol

Traceable author statement. Source: Reactome

neuron projection

Inferred from electronic annotation. Source: Ensembl

   Molecular_functionNADP binding

Inferred from electronic annotation. Source: Ensembl

flavin adenine dinucleotide binding

Inferred from electronic annotation. Source: Ensembl

methylenetetrahydrofolate reductase (NAD(P)H) activity

Traceable author statement. Source: Reactome

modified amino acid binding

Inferred from direct assay PubMed 20031578. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P42898-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: P42898-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MDHRKARVLPAGHYCPSLGIWASQVGSVRSSVPPSISRNPAM

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 656656Methylenetetrahydrofolate reductase
PRO_0000190245

Regions

Nucleotide binding63 – 686NAD By similarity
Nucleotide binding94 – 952NAD and FAD By similarity
Nucleotide binding157 – 1593FAD By similarity
Nucleotide binding174 – 1752FAD By similarity
Nucleotide binding201 – 2044FAD By similarity

Sites

Active site631Proton donor/acceptor By similarity
Binding site1271FAD By similarity
Binding site1591Substrate By similarity
Binding site1971FAD By similarity
Binding site2101FAD By similarity
Binding site2171FAD By similarity
Binding site2281Substrate By similarity
Binding site3211Substrate By similarity
Binding site3251Substrate By similarity

Natural variations

Alternative sequence11M → MDHRKARVLPAGHYCPSLGI WASQVGSVRSSVPPSISRNP AM in isoform 2.
VSP_053744
Natural variant511R → P in MTHFRD. Ref.17
Corresponds to variant rs201618781 [ dbSNP | Ensembl ].
VAR_009530
Natural variant521R → Q in MTHFRD. Ref.13
VAR_004319
Natural variant681R → Q. Ref.5
Corresponds to variant rs2066472 [ dbSNP | Ensembl ].
VAR_014881
Natural variant1571R → Q in MTHFRD. Ref.9
VAR_004320
Natural variant2221A → V Common polymorphism; thermolabile; 50% reduced activity; at homozygosity reduces the risk for colorectal cancer in individuals with adequate folate status; decreased risk for adult acute leukemia; increased risk for FS-NTD. Ref.4 Ref.5 Ref.14 Ref.15 Ref.16 Ref.18 Ref.19 Ref.23 Ref.24 Ref.26
Corresponds to variant rs1801133 [ dbSNP | Ensembl ].
VAR_009528
Natural variant2271T → M in MTHFRD. Ref.13
VAR_004321
Natural variant2511P → L in MTHFRD. Ref.13
VAR_004322
Natural variant3231L → P in MTHFRD. Ref.17
VAR_009531
Natural variant3241N → S in MTHFRD. Ref.21
VAR_009532
Natural variant3251R → C in MTHFRD. Ref.13
VAR_004323
Natural variant3351R → C in MTHFRD. Ref.13
VAR_004324
Natural variant3391W → G in MTHFRD. Ref.21
VAR_009533
Natural variant3571R → C in MTHFRD. Ref.13
VAR_004325
Natural variant3771R → C in MTHFRD. Ref.17
VAR_009534
Natural variant3871G → D in MTHFRD. Ref.25
VAR_009535
Natural variant4221G → R. Ref.5
Corresponds to variant rs45571736 [ dbSNP | Ensembl ].
VAR_018857
Natural variant4281E → A Common polymorphism; thermolabile; decreased activity.
VAR_009529
Natural variant4291E → A Common polymorphism; thermolabile; decreased activity; decreased risk for adult acute leukemia. Ref.5 Ref.20 Ref.22 Ref.24
Corresponds to variant rs1801131 [ dbSNP | Ensembl ].
VAR_014882
Natural variant4701E → A. Ref.27
VAR_054158
Natural variant5191R → C. Ref.5
Corresponds to variant rs45496998 [ dbSNP | Ensembl ].
VAR_018858
Natural variant5191R → H.
Corresponds to variant rs45449298 [ dbSNP | Ensembl ].
VAR_050293
Natural variant5661G → E.
Corresponds to variant rs2274974 [ dbSNP | Ensembl ].
VAR_050294
Natural variant5721P → L in MTHFRD. Ref.25
VAR_009536
Natural variant5861E → K in MTHFRD. Ref.25
VAR_009537
Natural variant5941R → Q. Ref.5 Ref.8
Corresponds to variant rs2274976 [ dbSNP | Ensembl ].
VAR_018859
Natural variant6531T → M. Ref.5
Corresponds to variant rs35737219 [ dbSNP | Ensembl ].
VAR_018860

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified December 7, 2004. Version 3.
Checksum: F16E774833D054B8

FASTA65674,597
        10         20         30         40         50         60 
MVNEARGNSS LNPCLEGSAS SGSESSKDSS RCSTPGLDPE RHERLREKMR RRLESGDKWF 

        70         80         90        100        110        120 
SLEFFPPRTA EGAVNLISRF DRMAAGGPLY IDVTWHPAGD PGSDKETSSM MIASTAVNYC 

       130        140        150        160        170        180 
GLETILHMTC CRQRLEEITG HLHKAKQLGL KNIMALRGDP IGDQWEEEEG GFNYAVDLVK 

       190        200        210        220        230        240 
HIRSEFGDYF DICVAGYPKG HPEAGSFEAD LKHLKEKVSA GADFIITQLF FEADTFFRFV 

       250        260        270        280        290        300 
KACTDMGITC PIVPGIFPIQ GYHSLRQLVK LSKLEVPQEI KDVIEPIKDN DAAIRNYGIE 

       310        320        330        340        350        360 
LAVSLCQELL ASGLVPGLHF YTLNREMATT EVLKRLGMWT EDPRRPLPWA LSAHPKRREE 

       370        380        390        400        410        420 
DVRPIFWASR PKSYIYRTQE WDEFPNGRWG NSSSPAFGEL KDYYLFYLKS KSPKEELLKM 

       430        440        450        460        470        480 
WGEELTSEES VFEVFVLYLS GEPNRNGHKV TCLPWNDEPL AAETSLLKEE LLRVNRQGIL 

       490        500        510        520        530        540 
TINSQPNING KPSSDPIVGW GPSGGYVFQK AYLEFFTSRE TAEALLQVLK KYELRVNYHL 

       550        560        570        580        590        600 
VNVKGENITN APELQPNAVT WGIFPGREII QPTVVDPVSF MFWKDEAFAL WIERWGKLYE 

       610        620        630        640        650 
EESPSRTIIQ YIHDNYFLVN LVDNDFPLDN CLWQVVEDTL ELLNRPTQNA RETEAP 

« Hide

Isoform 2 [UniParc].

Checksum: 53BD7151AA16F795
Show »

FASTA69778,965

References

« Hide 'large scale' references
[1]"cDNA for human methylenetetrahydrofolate reductase."
Rozen R., Goyette P.
Patent number WO9533054, 07-DEC-1995
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]"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.
Mamm. Genome 9:652-656(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]"Revised translation initiation site of the human methylenetetrahydrofolate reductase (MTHFR)."
Homberger A., Linnebank M., Winter C., Rapp B., Koch H.G.
Submitted (MAR-1999) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[4]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT VAL-222.
Tissue: Subthalamic nucleus.
[5]NIEHS SNPs program
Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS GLN-68; VAL-222; ARG-422; ALA-429; CYS-519; GLN-594 AND MET-653.
[6]"The DNA sequence and biological annotation of human chromosome 1."
Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. expand/collapse author list , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.
Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT GLN-594.
Tissue: Lung.
[9]"Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification."
Goyette P., Sumner J.S., Milos R., Duncan A.M.V., Rosenblatt D.S., Matthews R.G., Rozen R.
Nat. Genet. 7:195-200(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-415 (ISOFORM 1), VARIANT HOMOCYSTINURIA GLN-157.
Tissue: Liver.
[10]Erratum
Goyette P., Sumner J.S., Milos R., Duncan A.M.V., Rosenblatt D.S., Matthews R.G., Rozen R.
Nat. Genet. 7:551-551(1994) [PubMed] [Europe PMC] [Abstract]
[11]"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.
Mamm. Genome 13:483-492(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] OF 1-71 (ISOFORM 2), ALTERNATIVE SPLICING.
[12]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[13]"Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency."
Goyette P., Frosst P., Rosenblatt D.S., Rozen R.
Am. J. Hum. Genet. 56:1052-1059(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS MTHFRD GLN-52; MET-227; LEU-251; CYS-325; CYS-335 AND CYS-357, SEQUENCE REVISION TO 177.
[14]"Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida."
van der Put N.M.J., Steegers-Theunissen R.P.M., Frosst P., Trijbels F.J.M., Eskes T.K.A.B., van den Heuvel L.P., Mariman E.C.M., den Heyer M., Rozen R., Blom H.J.
Lancet 346:1070-1071(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: ASSOCIATION OF VARIANT VAL-222 WITH SUSCEPTIBILITY TO FS-NTD.
[15]"A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase."
Frosst P., Blom H.J., Milos R., Goyette P., Sheppard C.A., Matthews R.G., Boers G.J.H., den Heijer M., Kluijtmans L.A.J., van den Heuvel L.P., Rozen R.
Nat. Genet. 10:111-113(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT VAL-222.
[16]"5,10 Methylenetetrahydrofolate reductase genetic polymorphism as a risk factor for neural tube defects."
Ou C.Y., Stevenson R.E., Brown V.K., Schwartz C.E., Allen W.P., Khoury M.J., Rozen R., Oakley G.P. Jr., Adams M.J. Jr.
Am. J. Med. Genet. 63:610-614(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: ASSOCIATION OF VARIANT VAL-222 WITH SUSCEPTIBILITY TO FS-NTD.
[17]"Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations in MTHFR."
Goyette P., Christensen B., Rosenblatt D.S., Rozen R.
Am. J. Hum. Genet. 59:1268-1275(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS MTHFRD PRO-51; PRO-323 AND CYS-377.
[18]"A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer."
Chen J., Giovannucci E., Kelsey K., Rimm E.B., Stampfer M.J., Colditz G.A., Spiegelman D., Willett W.C., Hunter D.J.
Cancer Res. 56:4862-4864(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: INVERSE ASSOCIATION OF VARIANT VAL-222 WITH COLORECTAL CANCER.
[19]"Worldwide distribution of a common methylenetetrahydrofolate reductase mutation."
Schneider J.A., Rees D.C., Liu Y.-T., Clegg J.B.
Am. J. Hum. Genet. 62:1258-1260(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT VAL-222.
[20]"A second mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?"
van der Put N.M.J., Gabreels F., Stevens E.M.B., Smeitink J.A.M., Trijbels F.J.M., Eskes T.K.A.B., van den Heuvel L.P., Blom H.J.
Am. J. Hum. Genet. 62:1044-1051(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT ALA-429.
[21]"Identification of four novel mutations in severe methylenetetrahydrofolate reductase deficiency."
Kluijtmans L.A.J., Wendel U., Stevens E.M.B., van den Heuvel L.P.W.J., Trijbels F.J.M., Blom H.J.
Eur. J. Hum. Genet. 6:257-265(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS MTHFRD SER-324 AND GLY-339.
[22]"A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity."
Weisberg I., Tran P., Christiensen B., Sibani S., Rozen R.
Mol. Genet. Metab. 64:169-172(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT ALA-429.
[23]"Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects."
Christensen B., Arbour L., Tran P., Leclerc D., Sabbaghian N., Platt R., Gilfix B.M., Rosenblatt D.S., Gravel R.A., Forbes P., Rozen R.
Am. J. Med. Genet. 84:151-157(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: ASSOCIATION OF VARIANT VAL-222 WITH SUSCEPTIBILITY TO FS-NTD.
[24]"Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults."
Skibola C.F., Smith M.T., Kane E., Roman E., Rollinson S., Cartwright R.A., Morgan G.
Proc. Natl. Acad. Sci. U.S.A. 96:12810-12815(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS VAL-222 AND ALA-429, ASSOCIATION WITH SUSCEPTIBILITY TO ACUTE LEUKEMIA.
[25]"Characterization of six novel mutations in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with homocystinuria."
Sibani S., Christensen B., O'Ferrall E., Saadi I., Hiou-Tim F., Rosenblatt D.S., Rozen R.
Hum. Mutat. 15:280-287(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS MTHFRD ASP-387; LEU-572 AND LYS-586.
[26]"Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls."
Casas J.P., Hingorani A.D., Bautista L.E., Sharma P.
Arch. Neurol. 61:1652-1661(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: ASSOCIATION OF VARIANT VAL-222 WITH SUSCEPTIBILITY TO ISCHSTR.
[27]"DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome."
Ley T.J., Mardis E.R., Ding L., Fulton B., McLellan M.D., Chen K., Dooling D., Dunford-Shore B.H., McGrath S., Hickenbotham M., Cook L., Abbott R., Larson D.E., Koboldt D.C., Pohl C., Smith S., Hawkins A., Abbott S. expand/collapse author list , Locke D., Hillier L.W., Miner T., Fulton L., Magrini V., Wylie T., Glasscock J., Conyers J., Sander N., Shi X., Osborne J.R., Minx P., Gordon D., Chinwalla A., Zhao Y., Ries R.E., Payton J.E., Westervelt P., Tomasson M.H., Watson M., Baty J., Ivanovich J., Heath S., Shannon W.D., Nagarajan R., Walter M.J., Link D.C., Graubert T.A., DiPersio J.F., Wilson R.K.
Nature 456:66-72(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT [LARGE SCALE ANALYSIS] ALA-470.
+Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology
NIEHS-SNPs
SHMPD

The Singapore human mutation and polymorphism database

Wikipedia

Methylenetetrahydrofolate reductase entry

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U09806 mRNA. Translation: AAA74440.2.
AF105987 expand/collapse EMBL AC list , AF105977, AF105978, AF105979, AF105980, AF105981, AF105982, AF105983, AF105984, AF105985, AF105986 Genomic DNA. Translation: AAD17965.1.
AJ237672 mRNA. Translation: CAB41971.1.
AK312907 mRNA. Translation: BAG35753.1.
AY338232 Genomic DNA. Translation: AAP88033.1.
AL953897 Genomic DNA. Translation: CAI15885.1.
CH471130 Genomic DNA. Translation: EAW71709.1.
BC053509 mRNA. Translation: AAH53509.1.
AY046562 mRNA. Translation: AAL17648.1.
AF398930 Genomic DNA. Translation: AAN40865.1.
CCDSCCDS137.1.
PIRS46454.
RefSeqNP_005948.3. NM_005957.4. [P42898-1]
XP_005263515.1. XM_005263458.1. [P42898-2]
XP_005263517.1. XM_005263460.2. [P42898-1]
XP_005263518.1. XM_005263461.2. [P42898-1]
XP_005263519.1. XM_005263462.2. [P42898-1]
UniGeneHs.214142.
Hs.737916.

3D structure databases

ProteinModelPortalP42898.
SMRP42898. Positions 60-338.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid110624. 1 interaction.
IntActP42898. 1 interaction.
STRING9606.ENSP00000365775.

Chemistry

DrugBankDB00542. Benazepril.
DB00115. Cyanocobalamin.
DB00158. Folic Acid.
DB00134. L-Methionine.
DB00170. Menadione.
DB00563. Methotrexate.
DB00114. Pyridoxal Phosphate.
DB00165. Pyridoxine.
DB00293. Raltitrexed.
DB00140. Riboflavin.
DB00118. S-Adenosylmethionine.
DB00116. Tetrahydrofolic acid.

PTM databases

PhosphoSiteP42898.

Polymorphism databases

DMDM56405339.

Proteomic databases

MaxQBP42898.
PaxDbP42898.
PRIDEP42898.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000376583; ENSP00000365767; ENSG00000177000.
ENST00000376590; ENSP00000365775; ENSG00000177000.
ENST00000376592; ENSP00000365777; ENSG00000177000.
GeneID4524.
KEGGhsa:4524.
UCSCuc001atc.2. human. [P42898-1]

Organism-specific databases

CTD4524.
GeneCardsGC01M011845.
HGNCHGNC:7436. MTHFR.
MIM236250. phenotype.
601367. phenotype.
601634. phenotype.
603174. phenotype.
607093. gene.
neXtProtNX_P42898.
Orphanet268392. Cervical spina bifida aperta.
268762. Cervical spina bifida cystica.
268397. Cervicothoracic spina bifida aperta.
268766. Cervicothoracic spina bifida cystica.
395. Homocystinuria due to methylene tetrahydrofolate reductase deficiency.
1048. Isolated anencephaly/exencephaly.
268388. Lumbosacral spina bifida aperta.
268758. Lumbosacral spina bifida cystica.
90070. Methotrexate poisoning.
64738. Non rare thrombophilia.
240977. Susceptibility to adverse reaction due to methotrexate treatment.
268384. Thoracolumbosacral spina bifida aperta.
268752. Thoracolumbosacral spina bifida cystica.
268377. Total spina bifida aperta.
268748. Total spina bifida cystica.
268740. Upper thoracic spina bifida aperta.
268770. Upper thoracic spina bifida cystica.
PharmGKBPA245.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0685.
HOGENOMHOG000246234.
HOVERGENHBG006414.
InParanoidP42898.
KOK00297.
OMAYLEFFVS.
OrthoDBEOG7TF7B4.
PhylomeDBP42898.
TreeFamTF105665.

Enzyme and pathway databases

ReactomeREACT_111217. Metabolism.
REACT_116125. Disease.
SABIO-RKP42898.
UniPathwayUPA00193.

Gene expression databases

ArrayExpressP42898.
BgeeP42898.
CleanExHS_MTHFR.
GenevestigatorP42898.

Family and domain databases

Gene3D3.20.20.220. 1 hit.
InterProIPR029041. FAD-linked_oxidoreductase-like.
IPR004621. Fadh2_euk.
IPR003171. Mehydrof_redctse.
[Graphical view]
PfamPF02219. MTHFR. 1 hit.
[Graphical view]
SUPFAMSSF51730. SSF51730. 1 hit.
TIGRFAMsTIGR00677. fadh2_euk. 1 hit.
ProtoNetSearch...

Other

ChiTaRSMTHFR. human.
GeneWikiMethylenetetrahydrofolate_reductase.
GenomeRNAi4524.
NextBio17474.
PROP42898.
SOURCESearch...

Entry information

Entry nameMTHR_HUMAN
AccessionPrimary (citable) accession number: P42898
Secondary accession number(s): B2R7A6 expand/collapse secondary AC list , Q5SNW6, Q5SNW9, Q7Z6M6, Q8IU73, Q9UQR2
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: December 7, 2004
Last modified: July 9, 2014
This is version 141 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PATHWAY comments

Index of metabolic and biosynthesis pathways

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 1

Human chromosome 1: entries, gene names and cross-references to MIM