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DHFR (dihydrofolate reductase)

Written2015-12Maja Krajinovic, Rachid Abaji, Bahram Sharif-Askari
Research Center, CHU Sainte-Justine, Montreal, QC, Canada (MK, RA, BSA); Department of Pediatrics, University of Montreal, Canada (MK); 3-Department of Pharmacology, University of Montreal, Canada (MK, RA, BSA) Maja.krajinovic@umontreal.ca; rasheed3000@hotmail.com; bahram_sharif@hotmail.com

Abstract Dihydrofolate reductase (DHFR) is a member of the reductase enzyme family, which is ubiquitously expressed in all organisms. Levels of this enzyme peak at the G1/S cell cycle boundary. Autoregulation, through DHFR-RNA interactions, has also been reported. DHFR catalyzes the NADPH dependent reduction of dihydrofolate (DHF) to tetrahydrofolate (THF) needed for several one-carbon transfer reactions in purine and pyrimidine synthesis (Jensen et al 1997, Klon et al 2002). It is also the only enzyme that reduces folic acid, a synthetic vitamin not found in nature, to dihydrofolate (Banka et al. 2011). Reduction of DHFR enzymatic activity diminishes the THF pool inside the cell which slows DNA synthesis and cell proliferation eventually leading to cell death (Assaraf et al 2007, Klon et al 2002, Morales et al 2009). DHFR inhibition is essential to the action of antifolate medications used to treat cancer and some inflammatory diseases. Changes in DHFR expression can affect susceptibility to a variety of diseases dependent on folate status such as spina bifida and cancer. Likewise, human DHFR (hDHFR) has become a major drug target in anticancer therapy (Klon et al 2002, Sharif-Askari et al 2010).

Keywords Dihydrofolate (DHF), Tetrahydrofolate (THF), Folate-dependent enzymes, DNA synthesis.

(Note : for Links provided by Atlas : click)

Identity

Other aliasDHFRP1
DYR
EC 1.5 1.3
HGNC (Hugo) DHFR
LocusID (NCBI) 1719
Atlas_Id 40303
Location 5q14.1  [Link to chromosome band 5q14]
Location_base_pair Starts at 80626226 and ends at 80654981 bp from pter ( according to hg19-Feb_2009)  [Mapping DHFR.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
DHFR (5q14.1) / LSP1 (11p15.5)DHFR (5q14.1) / PSMD2 (3q27.1)DHFR (5q14.1) / SPPL3 (12q24.31)
DHFR (5q14.1) / TM9SF3 (10q24.1)GSS (20q11.22) / DHFR (5q14.1)ZMIZ1 (10q22.3) / DHFR (5q14.1)
ZNF483 (9q31.3) / DHFR (5q14.1)

DNA/RNA

Description DHFR encoded on chromosome 5 and has 6 exons which are separated by 5 introns.
Chen et al (1984) determined that the DHFR gene is about 30 kb long and consists of 6 exons separated by 5 introns. The full length transcript is 28756 bp long and length of 3'-UTR of some human DHFR mRNA molecules was found to be 2900 nucleotides (Chen et al 1984).
Transcription The human DHFR contains two promoters, the minor transcript which represents only 1% of DHFR mRNA molecules and the major transcript which codes for 99% DHFR mRNA. Independent regulation, low prevalence, nuclear enrichment and low translational efficiency suggest that the DHFR minor transcript may function in vivo to regulate the transcriptional activity of the major promoter (Blume et al 2003 and Martianov et al 2007).
Pseudogene The DHFR gene family includes the functional DHFR gene and four other intronless pseudogenes, dihydrofolate reductase pseudogene (DHFRP1-4), based on human-rodent somatic cell hybridization. Pseudogene-4 (DHFRP4) is assigned to chromosome 3, pseudogene-1 to chromosome 18 with two transcripts and pseudogene-2 (DHFRP2) to chromosome 6 with one transcript (Anagnou et al. 1984 and Anagnou et al. 1985). Interestingly, according to Anagnou et al. 1988 report, pseudogene-1 (DHFRP1) was found to be present in some individuals while completely absent in others with an interethnic variation in frequency which might implicate a recent origin in the evolutionary process (Anagnou et al., 1988).
Recent studies suggest that DHFRP4, now known as dihydrofolate reductase-like 1 (DHFRL1) is expressed giving a functional protein product which shows a similar but less specific activity to that of DHFR enzyme (McEntee et al 2011).

Protein

Description Sequence length: 187 AA. Craik et al. (1983) in DHFR protein study reported that altered surface structures can account for functional differences among the members of a family. Also they pointed out that 'sliding' of the intron-exon junctions may design a mechanism for generating length polymorphisms and divergent sequences.
Expression DHFR is extensively expressed in the fetal and adult tissues such as heart, liver, skeletal muscle, thymus, kidney, brains and whole blood with higher expression in adult brain in compare to fetal brain (Banka et al 2011).
Localisation While the dihydrofolate reductase enzyme is thought to be present in multiple cellular compartments, it is most particularly localized in the cytosol and the nucleoplasm.
Function DHFR is a key enzyme in folate metabolism as it is involved in 5,10-methylene tetra hydro folate (THF) generation from 7,8-dihydrofolate (DHF). The generated 5,10-methylene THF is used for the conversion of deoxyuridylate (dUMP) to deoxythymidylate (dTMP) in a reaction catalyzed by thymidylate synthase (TS). The regenerated THF starts subsequent rounds of thymidylate biosynthesis. Moreover DHFR contributes to the de novo mitochondrial thymidylate biosynthesis pathway and catalyzes de novo glycine and purine synthesis as well as DNA precursor synthesis (Anderson et al 2011 and Assaraf et al 2007).
Homology Funanage et al (1984) assigned the DHFR gene to chromosome 5 and further narrowed the assignment to 5q11-q22. Based on their evidences, there is a homology between both the short and long arm of hamster chromosome 2 and human chromosome 5. Also, the sequences of the human and mouse DHFR proteins studied by Chen et al was shown to differ in only 21 of 186 amino acids, which reflects an 89% homology in the DNA coding sequences of the genes (Funanage et al 1984 and Chen et al 1984).

Mutations

Germinal
  • Germline polymorphisms
    1. Location: Intron 1
    Polymorphism: 19-bp insertion /deletion (rs70991108
    Impact: Low-serum folate/ high homocysteine, change in mRNA levels
    Related disorders: Neural tube defects and breast cancer
    Note: 19 base pair deletion in intron 1 which elevated risk of developing breast cancer, neural-tube defects (NTD) and may be a risk factor for low birth weight and preterm delivery (Xu et al 2007, Vander linden 2006 and Johnson et al 2005). In contrast, Parle-McDermott et al (2007), demonstrated that 19-bp deletion allele (D) may be a protective genetic factor against NTD by increasing DHFR mRNA levels in pregnant women. Moreover, a study by Rafighdoost also suggests that DHFR 19-bp D/D genotype reduce the risk of Nonsyndromic cleft lip with or without cleft palate (NS-CL/P) in Iranian subjects (Rafighdoost et al. 2015).
    Ongaro et al (2009) and Vagace et al (2011) reported that homozygosity for DHFR 19 bp deleted allele polymorphism has been associated with increased hepatotoxicity in leukemia patients treated with MTX.

    2. Location: 3'-UTR
    Polymorphism: C829T, A721T, A1171T
    Impact: MTX resistance
    Related disorder: NTD and Rheumatoid Arthritis
    Note: C829T: Goto et al., (2001), by analyzing 3' untranslated region (UTR) of the human DHFR gene transcript discovered C829T substitution located 223 base pairs downstream from the stop codon and positioned between the first and second polyadenylation site. It interferes with miR-24 function leading to higher DHFR mRNA and protein levels. Present in 14.2% of the Japanese populations, the 829T/T mRNA expression level was found to be higher than 829C/C due to the higher stability of the T/T mRNA (Goto et al, 2001).
    A721T did not have and significant association with NTD, but was found to be in complete linkage disequilibrium (LD) with the 19-bp indel polymorphism. (Parle-McDermott et al 2007).
    Sharma et al (2009) demonstrated that DHFR A1171T (rs7387) polymorphism located in 3'UTR is considered as putative predictor for MTX response in rheumatoid arthritis patients.

    3. Location: Downstream to 3'UTR
    Polymorphism: A35289G (rs1232027)
    Related disorder: MTX efficacy in patients with psoriatic arthritis.
    Note: Chandran et al (2010) found an association of the A allele of A35289G polymorphism with MTX efficacy in patients with psoriatic arthritis.

    4. Location: Minor promoter
    Polymorphism: C-1610G or T (rs1650694) and A-317/G (rs408626)
    Impact: Higher DHFR expression
    Related disorder: Higher risk of relapse in ALL
    Note: Three polymorphisms in DHFR promoter in the 2 kb region upstream of the first or minor transcription of DHFR gene, (C-1610G/T, C-680A, and A-317G) were found associated with treatment responses in children with acute lymphoblastic leukemia (ALL). Haplotype 1 contains both the A-317 and C-1610 alleles and conferred higher transcriptional activity, as shown by reporter gene assay and quantitative mRNA analysis, likely explaining a worse prognosis in patients carrying this haplotype. The ALL patients who were carriers of this haplotype had reduced event free survival (EFS) (Dulucq et al 2008).

    5. Location: Major promoter
    Polymorphism: G308A (rs1105525), C35T (rs1650697), Length polymorphism 63/91: 9-bp insertion deletion/ 9-bp repeat (rs3045983/ - )
    Impact: Higher DHFR expression
    Related disorder: Higher risk of relapse in ALL
    Note: Six polymorphisms including five SNPs, C35T, C304T, G308A, G319A, and A413G substitutions, along with one length polymorphism composed of two sequence motifs (i.e. insertion/deletion at position 63 and variable number of 9-bp elements at position 91), were identified in the major promoter of DHFR which participate in regulation as both a major promoter and a noncoding minor transcript. Haplotype 1b was identified as a haplotype responsible for the lower relapse-free survival observed in ALL patients. This haplotype is defined by C-1610, C-680, A-317 in the minor promoter and three alleles (T35, A308 and compound length polymorphisms composed of 9-base pair (bp) insertion at position 63 and triple 9bp element at position 91) in the major promoter (Dulucq et al 2008 and Al-Shakfa, et al 2009).

    6. Location: Intron 3
    Polymorphism: A10372C (rs1677693) and A8890G (rs1643659)
    Related disorder: Colorectal cancer (Levine AJ et al 2010).

    Polymorphism: 79940143T>C (rs1643650)
    Related disorder: Rheumatoid Arthritis
    Note: According to Salazar et al, this polymorphism was significantly associated with response to MTX in rheumatoid arthritis patients; patients with C/C and C/T genotypes showed a better response to treatment that those with T/T (Salazar et al 2014).

  • Mutations
    Location: 458A>T (Asp153Val)
    Related disorder: Megaloblastic Anemia.
    Note: Cario et al., 2011 reported a homozygous DHFR mutation, 458A>T (Asp153Val) that leads to DHFR deficiency which in turn results in a complex hematological and neurological disease that can be successfully resolved with folic acid or folinic acid replacement (Banka et al 2011 and Cario et al., 2011).
  • Implicated in

    Note
      
    Entity Megaloblastic anemia
    Note Dihydrofolate reductase deficiency is an autosomal recessive metabolic disorder characterized by the hematologic findings of megaloblastic anemia and variable neurologic symptoms.
    A germline missense mutation in DHFR was identified causing subsequent extensive enzyme deficiency and resulting in an inborn error of metabolism which is characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency (Banka et al 2011).
      
      
    Entity Neural tube defects (NTD)
    Note Neural tube closure occurs during a period of rapid cellular proliferation and DHFR activity may be a crucial factor in maintaining optimal DNA synthesis during this time. Changes in the activity of the folate cycle enzymes may affect the folate levels and affect NTD development. The most extensively studied DHFR polymorphism is a 19bp insertion to deletion in the first intron and two polymorphisms within the 3' untranslated region (721A>T and 829C>T) of the DHFR gene (Parle-McDermott et al 2007).
      
      
    Entity Rheumatoid Arthritis (RA)
    Note Response to treatment with Methotrexate in RA treatment was found to be influenced by the genotypes of the DHFR polymorphisms rs7387 (Sharma et al 2009) and rs1643650 (Salazar et al 2014).
      
      
    Entity Breast cancer
    Note The DHFR 19-bp deletion polymorphism affects the transcription of DHFR gene in humans which can modify the risk of breast cancer in multivitamin supplement users. A multivitamin supplement has adverse effects in patients carrying the 19-bp insertion allele (Xu et al 2007).
      
      
    Entity Colorectal cancer (CRC)
    Note Levine et al, 2010 demonstrated significant associations between two DHFR tagSNPs (rs1677693 and rs1643659, located on the third intron of the gene) and CRC risk only in individuals not using multivitamin supplements.
      
      
    Entity Retinoblastoma
    Note Risk of retinoblastoma was significantly elevated among children of mothers homozygous for the 19bp deletion allele taking prenatal synthetic folic acid supplements (Orjuela, et al 2012).
      
      
    Entity Nasopharyngeal carcinoma (NPC)
    Note DHFR has a significantly higher expression in NPC and is involved in NPC progression through the nucleotide biosynthetic process (Lee et al 2013).
      
      
    Entity Acute lymphoblastic leukemia (ALL)
    Note MTX is an important component of maintenance therapy in ALL, it exerts its cytotoxicity function by depletion of reduced folates due to interfering with folate metabolism. Changes in DHFR expression level has been found to correlate with MTX efficacy in ALL (Ongaro et al 2009). Polymorphisms in DHFR gene may affect therapeutic responses to antifolates, leading to lower treatment efficacy or higher adverse drug event frequency. Particular haplotype (1b) increases mRNA levels of DHFR and was associated with a higher risk of ALL relapse.
      

    Bibliography

    Personal Communication
    Myoda, T. T. and Funanage, V. L.
    Wilmington, Del. 10/7/1983.
     
    DNA variants in region for noncoding interfering transcript of dihydrofolate reductase gene and outcome in childhood acute lymphoblastic leukemia
    Al-Shakfa F, Dulucq S, Brukner I, Milacic I, Ansari M, Beaulieu P, Moghrabi A, Laverdière C, Sallan SE, Silverman LB, Neuberg D, Kutok JL, Sinnett D, Krajinovic M
    Clin Cancer Res 2009 Nov 15;15(22):6931-8
    PMID 19861437
     
    A novel form of human polymorphism involving the hDHFR-psi 1 pseudogene identifies three RFLPs
    Anagnou NP, Antonarakis SE, O'Brien SJ, Nienhuis AW
    Nucleic Acids Res 1987 Jul 10;15(13):5501
    PMID 2885811
     
    Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria
    Anderson DD, Quintero CM, Stover PJ
    Proc Natl Acad Sci U S A 2011 Sep 13;108(37):15163-8
    PMID 21876188
     
    Dihydrofolate reductase gene variations in susceptibility to disease and treatment outcomes
    Askari BS, Krajinovic M
    Curr Genomics 2010 Dec;11(8):578-83
    PMID 21629435
     
    Molecular basis of antifolate resistance
    Assaraf YG
    Cancer Metastasis Rev 2007 Mar;26(1):153-81
    PMID 17333344
     
    Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency
    Banka S, Blom HJ, Walter J, Aziz M, Urquhart J, Clouthier CM, Rice GI, de Brouwer AP, Hilton E, Vassallo G, Will A, Smith DE, Smulders YM, Wevers RA, Steinfeld R, Heales S, Crow YJ, Pelletier JN, Jones S, Newman WG
    Am J Hum Genet 2011 Feb 11;88(2):216-25
    PMID 21310276
     
    The 5'-untranslated RNA of the human dhfr minor transcript alters transcription pre-initiation complex assembly at the major (core) promoter
    Blume SW, Meng Z, Shrestha K, Snyder RC, Emanuel PD
    J Cell Biochem 2003 Jan 1;88(1):165-80
    PMID 12461786
     
    Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease
    Cario H, Smith DE, Blom H, Blau N, Bode H, Holzmann K, Pannicke U, Hopfner KP, Rump EM, Ayric Z, Kohne E, Debatin KM, Smulders Y, Schwarz K
    Am J Hum Genet 2011 Feb 11;88(2):226-31
    PMID 21310277
     
    Folate pathway enzyme gene polymorphisms and the efficacy and toxicity of methotrexate in psoriatic arthritis
    Chandran V, Siannis F, Rahman P, Pellett FJ, Farewell VT, Gladman DD
    J Rheumatol 2010 Jul;37(7):1508-12
    PMID 20472929
     
    The functional human dihydrofolate reductase gene
    Chen MJ, Shimada T, Moulton AD, Cline A, Humphries RK, Maizel J, Nienhuis AW
    J Biol Chem 1984 Mar 25;259(6):3933-43
    PMID 6323448
     
    Splice junctions: association with variation in protein structure
    Craik CS, Rutter WJ, Fletterick R
    Science 1983 Jun 10;220(4602):1125-9
    PMID 6344214
     
    DNA variants in the dihydrofolate reductase gene and outcome in childhood ALL
    Dulucq S, St-Onge G, Gagné V, Ansari M, Sinnett D, Labuda D, Moghrabi A, Krajinovic M
    Blood 2008 Apr 1;111(7):3692-700
     
    Assignment of the human dihydrofolate reductase gene to the q11----q22 region of chromosome 5
    Funanage VL, Myoda TT, Moses PA, Cowell HR
    Mol Cell Biol 1984 Oct;4(10):2010-6
    PMID 6504041
     
    A novel single-nucleotide polymorphism in the 3'-untranslated region of the human dihydrofolate reductase gene with enhanced expression
    Goto Y, Yue L, Yokoi A, Nishimura R, Uehara T, Koizumi S, Saikawa Y
    Clin Cancer Res 2001 Jul;7(7):1952-6
    PMID 11448909
     
    Distinct roles for Sp1 and E2F sites in the growth/cell cycle regulation of the DHFR promoter
    Jensen DE, Black AR, Swick AG, Azizkhan JC
    J Cell Biochem 1997 Oct 1;67(1):24-31
    PMID 9328836
     
    Common dihydrofolate reductase 19-base pair deletion allele: a novel risk factor for preterm delivery
    Johnson WG, Scholl TO, Spychala JR, Buyske S, Stenroos ES, Chen X
    Am J Clin Nutr 2005 Mar;81(3):664-8
    PMID 15755837
     
    Atomic structures of human dihydrofolate reductase complexed with NADPH and two lipophilic antifolates at 1
    Klon AE, Héroux A, Ross LJ, Pathak V, Johnson CA, Piper JR, Borhani DW
    09 a and 1 05 a resolution
    PMID 12096917
     
    Overexpression of thymidylate synthetase confers an independent prognostic indicator in nasopharyngeal carcinoma
    Lee SW, Chen TJ, Lin LC, Li CF, Chen LT, Hsing CH, Hsu HP, Tsai CJ, Huang HY, Shiue YL
    Exp Mol Pathol 2013 Aug;95(1):83-90
    PMID 23726796
     
    A candidate gene study of folate-associated one carbon metabolism genes and colorectal cancer risk
    Levine AJ, Figueiredo JC, Lee W, Conti DV, Kennedy K, Duggan DJ, Poynter JN, Campbell PT, Newcomb P, Martinez ME, Hopper JL, Le Marchand L, Baron JA, Limburg PJ, Ulrich CM, Haile RW
    Cancer Epidemiol Biomarkers Prev 2010 Jul;19(7):1812-21
    PMID 20615890
     
    Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript
    Martianov I, Ramadass A, Serra Barros A, Chow N, Akoulitchev A
    Nature 2007 Feb 8;445(7128):666-70
    PMID 17237763
     
    The former annotated human pseudogene dihydrofolate reductase-like 1 (DHFRL1) is expressed and functional
    McEntee G, Minguzzi S, O'Brien K, Ben Larbi N, Loscher C, O'Fágáin C, Parle-McDermott A
    Proc Natl Acad Sci U S A 2011 Sep 13;108(37):15157-62
    PMID 21876184
     
    Dihydrofolate reductase amplification and sensitization to methotrexate of methotrexate-resistant colon cancer cells
    Morales C, García MJ, Ribas M, Miró R, Muñoz M, Caldas C, Peinado MA
    Mol Cancer Ther 2009 Feb;8(2):424-32
    PMID 19190117
     
    Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival
    Ongaro A, De Mattei M, Della Porta MG, Rigolin G, Ambrosio C, Di Raimondo F, Pellati A, Masieri FF, Caruso A, Catozzi L, Gemmati D
    Haematologica 2009 Oct;94(10):1391-8
    PMID 19648163
     
    Risk of retinoblastoma is associated with a maternal polymorphism in dihydrofolatereductase (DHFR) and prenatal folic acid intake
    Orjuela MA, Cabrera-Muñoz L, Paul L, Ramirez-Ortiz MA, Liu X, Chen J, Mejia-Rodriguez F, Medina-Sanson A, Diaz-Carreño S, Suen IH, Selhub J, Ponce-Castañeda MV
    Cancer 2012 Dec 1;118(23):5912-9
    PMID 22648968
     
    The 19-bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR) may decrease rather than increase risk for spina bifida in the Irish population
    Parle-McDermott A, Pangilinan F, Mills JL, Kirke PN, Gibney ER, Troendle J, O'Leary VB, Molloy AM, Conley M, Scott JM, Brody LC
    Am J Med Genet A 2007 Jun 1;143A(11):1174-80
    PMID 17486595
     
    The 19-bp deletion polymorphism of dihydrofolate reductase (DHFR) and nonsyndromic cleft lip with or without cleft palate: evidence for a protective role
    Rafighdoost F, Rafighdoost A, Rafighdoost H, Rigi-Ladez MA, Hashemi M, Eskandari-Nasab E
    J Appl Oral Sci 2015 May-Jun;23(3):272-8
    PMID 26221921
     
    Polymorphisms in genes involved in the mechanism of action of methotrexate: are they associated with outcome in rheumatoid arthritis patients? Pharmacogenomics
    Salazar J, Moya P, Altés A, Díaz-Torné C, Casademont J, Cerdà-Gabaroi D, Corominas H, Baiget M
    2014 Jun;15(8):1079-90 doi: 10
    PMID 25084201
     
    Purine biosynthetic pathway genes and methotrexate response in rheumatoid arthritis patients among north Indians
    Sharma S, Das M, Kumar A, Marwaha V, Shankar S, Singh P, Raghu P, Aneja R, Grover R, Arya V, Dhir V, Gupta R, Kumar U, Juyal RC, K TB
    Pharmacogenet Genomics 2009 Oct;19(10):823-8
    PMID 19902562
     
    Methotrexate-induced subacute neurotoxicity in a child with acute lymphoblastic leukemia carrying genetic polymorphisms related to folate homeostasis
    Vagace JM, Caceres-Marzal C, Jimenez M, Casado MS, de Murillo SG, Gervasini G
    Am J Hematol 2011 Jan;86(1):98-101
    PMID 21064136
     
    A functional 19-base pair deletion polymorphism of dihydrofolate reductase (DHFR) and risk of breast cancer in multivitamin users
    Xu X, Gammon MD, Wetmur JG, Rao M, Gaudet MM, Teitelbaum SL, Britton JA, Neugut AI, Santella RM, Chen J
    Am J Clin Nutr 2007 Apr;85(4):1098-102
    PMID 17413111
     
    Genetic variation in genes of folate metabolism and neural-tube defect risk
    van der Linden IJ, Afman LA, Heil SG, Blom HJ
    Proc Nutr Soc 2006 May;65(2):204-15
    PMID 16672082
     

    Citation

    This paper should be referenced as such :
    Krajinovic M, Abaji R, Sharif-Askari B
    DHFR (dihydrofolate reductase);
    Atlas Genet Cytogenet Oncol Haematol. in press
    On line version : http://AtlasGeneticsOncology.org/Genes/DHFRID40303ch5q14.html


    External links

    Nomenclature
    HGNC (Hugo)DHFR   2861
    Cards
    AtlasDHFRID40303ch5q14
    Entrez_Gene (NCBI)DHFR  1719  dihydrofolate reductase
    AliasesDHFRP1; DYR
    GeneCards (Weizmann)DHFR
    Ensembl hg19 (Hinxton)ENSG00000228716 [Gene_View]
    Ensembl hg38 (Hinxton)ENSG00000228716 [Gene_View]  chr5:80626226-80654981 [Contig_View]  DHFR [Vega]
    ICGC DataPortalENSG00000228716
    TCGA cBioPortalDHFR
    AceView (NCBI)DHFR
    Genatlas (Paris)DHFR
    WikiGenes1719
    SOURCE (Princeton)DHFR
    Genetics Home Reference (NIH)DHFR
    Genomic and cartography
    GoldenPath hg38 (UCSC)DHFR  -     chr5:80626226-80654981 -  5q14.1   [Description]    (hg38-Dec_2013)
    GoldenPath hg19 (UCSC)DHFR  -     5q14.1   [Description]    (hg19-Feb_2009)
    EnsemblDHFR - 5q14.1 [CytoView hg19]  DHFR - 5q14.1 [CytoView hg38]
    Mapping of homologs : NCBIDHFR [Mapview hg19]  DHFR [Mapview hg38]
    OMIM126060   613839   
    Gene and transcription
    Genbank (Entrez)AA489055 AK293146 AK297302 AK308492 AK312642
    RefSeq transcript (Entrez)NM_000791 NM_001290354 NM_001290357
    RefSeq genomic (Entrez)
    Consensus coding sequences : CCDS (NCBI)DHFR
    Cluster EST : UnigeneHs.648635 [ NCBI ]
    CGAP (NCI)Hs.648635
    Alternative Splicing GalleryENSG00000228716
    Gene ExpressionDHFR [ NCBI-GEO ]   DHFR [ EBI - ARRAY_EXPRESS ]   DHFR [ SEEK ]   DHFR [ MEM ]
    Gene Expression Viewer (FireBrowse)DHFR [ Firebrowse - Broad ]
    SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
    GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)1719
    GTEX Portal (Tissue expression)DHFR
    Human Protein AtlasENSG00000228716-DHFR [pathology]   [cell]   [tissue]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP00374   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
    NextProtP00374  [Sequence]  [Exons]  [Medical]  [Publications]
    With graphics : InterProP00374
    Splice isoforms : SwissVarP00374
    PhosPhoSitePlusP00374
    Domaine pattern : Prosite (Expaxy)DHFR_1 (PS00075)    DHFR_2 (PS51330)   
    Domains : Interpro (EBI)DHFR    DHFR-like_dom    DHFR_CS    DHFR_dom   
    Domain families : Pfam (Sanger)DHFR_1 (PF00186)   
    Domain families : Pfam (NCBI)pfam00186   
    Conserved Domain (NCBI)DHFR
    DMDM Disease mutations1719
    Blocks (Seattle)DHFR
    PDB (SRS)###############################################################################################################################################################################################################################################################   
    PDB (PDBSum)###############################################################################################################################################################################################################################################################   
    PDB (IMB)###############################################################################################################################################################################################################################################################   
    PDB (RSDB)###############################################################################################################################################################################################################################################################   
    Structural Biology KnowledgeBase###############################################################################################################################################################################################################################################################   
    SCOP (Structural Classification of Proteins)###############################################################################################################################################################################################################################################################   
    CATH (Classification of proteins structures)###############################################################################################################################################################################################################################################################   
    SuperfamilyP00374
    Human Protein Atlas [tissue]ENSG00000228716-DHFR [tissue]
    Peptide AtlasP00374
    HPRD00519
    IPIIPI00030357   IPI00968238   IPI00967478   
    Protein Interaction databases
    DIP (DOE-UCLA)P00374
    IntAct (EBI)P00374
    FunCoupENSG00000228716
    BioGRIDDHFR
    STRING (EMBL)DHFR
    ZODIACDHFR
    Ontologies - Pathways
    QuickGOP00374
    Ontology : AmiGOG1/S transition of mitotic cell cycle  regulation of transcription involved in G1/S transition of mitotic cell cycle  translation repressor activity, nucleic acid binding  mRNA binding  dihydrofolate reductase activity  dihydrofolate reductase activity  dihydrofolate reductase activity  folic acid binding  cellular_component  nucleoplasm  mitochondrion  cytosol  glycine biosynthetic process  tetrahydrobiopterin biosynthetic process  tetrahydrobiopterin biosynthetic process  one-carbon metabolic process  drug binding  nucleotide biosynthetic process  negative regulation of translation  axon regeneration  response to methotrexate  folate reductase activity  dihydrofolate metabolic process  tetrahydrofolate metabolic process  tetrahydrofolate biosynthetic process  tetrahydrofolate biosynthetic process  folic acid metabolic process  folic acid metabolic process  positive regulation of nitric-oxide synthase activity  methotrexate binding  oxidation-reduction process  NADPH binding  sequence-specific mRNA binding  regulation of removal of superoxide radicals  
    Ontology : EGO-EBIG1/S transition of mitotic cell cycle  regulation of transcription involved in G1/S transition of mitotic cell cycle  translation repressor activity, nucleic acid binding  mRNA binding  dihydrofolate reductase activity  dihydrofolate reductase activity  dihydrofolate reductase activity  folic acid binding  cellular_component  nucleoplasm  mitochondrion  cytosol  glycine biosynthetic process  tetrahydrobiopterin biosynthetic process  tetrahydrobiopterin biosynthetic process  one-carbon metabolic process  drug binding  nucleotide biosynthetic process  negative regulation of translation  axon regeneration  response to methotrexate  folate reductase activity  dihydrofolate metabolic process  tetrahydrofolate metabolic process  tetrahydrofolate biosynthetic process  tetrahydrofolate biosynthetic process  folic acid metabolic process  folic acid metabolic process  positive regulation of nitric-oxide synthase activity  methotrexate binding  oxidation-reduction process  NADPH binding  sequence-specific mRNA binding  regulation of removal of superoxide radicals  
    Pathways : BIOCARTACell Cycle: G1/S Check Point [Genes]   
    Pathways : KEGGOne carbon pool by folate    Folate biosynthesis   
    REACTOMEP00374 [protein]
    REACTOME PathwaysR-HSA-69205 [pathway]   
    NDEx NetworkDHFR
    Atlas of Cancer Signalling NetworkDHFR
    Wikipedia pathwaysDHFR
    Orthology - Evolution
    OrthoDB1719
    GeneTree (enSembl)ENSG00000228716
    Phylogenetic Trees/Animal Genes : TreeFamDHFR
    HOVERGENP00374
    HOGENOMP00374
    Homologs : HomoloGeneDHFR
    Homology/Alignments : Family Browser (UCSC)DHFR
    Gene fusions - Rearrangements
    Polymorphisms : SNP and Copy number variants
    NCBI Variation ViewerDHFR [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)DHFR
    dbVarDHFR
    ClinVarDHFR
    1000_GenomesDHFR 
    Exome Variant ServerDHFR
    ExAC (Exome Aggregation Consortium)ENSG00000228716
    GNOMAD BrowserENSG00000228716
    Genetic variants : HAPMAP1719
    Genomic Variants (DGV)DHFR [DGVbeta]
    DECIPHERDHFR [patients]   [syndromes]   [variants]   [genes]  
    CONAN: Copy Number AnalysisDHFR 
    Mutations
    ICGC Data PortalDHFR 
    TCGA Data PortalDHFR 
    Broad Tumor PortalDHFR
    OASIS PortalDHFR [ Somatic mutations - Copy number]
    Somatic Mutations in Cancer : COSMICDHFR  [overview]  [genome browser]  [tissue]  [distribution]  
    Mutations and Diseases : HGMDDHFR
    LOVD (Leiden Open Variation Database)Whole genome datasets
    LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
    LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
    BioMutasearch DHFR
    DgiDB (Drug Gene Interaction Database)DHFR
    DoCM (Curated mutations)DHFR (select the gene name)
    CIViC (Clinical Interpretations of Variants in Cancer)DHFR (select a term)
    intoGenDHFR
    NCG5 (London)DHFR
    Cancer3DDHFR(select the gene name)
    Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
    Diseases
    OMIM126060    613839   
    Orphanet21687   
    MedgenDHFR
    Genetic Testing Registry DHFR
    NextProtP00374 [Medical]
    TSGene1719
    GENETestsDHFR
    Target ValidationDHFR
    Huge Navigator DHFR [HugePedia]
    snp3D : Map Gene to Disease1719
    BioCentury BCIQDHFR
    ClinGenDHFR
    Clinical trials, drugs, therapy
    Chemical/Protein Interactions : CTD1719
    Chemical/Pharm GKB GenePA143
    Clinical trialDHFR
    Miscellaneous
    canSAR (ICR)DHFR (select the gene name)
    Probes
    Litterature
    PubMed156 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    CoreMineDHFR
    EVEXDHFR
    GoPubMedDHFR
    iHOPDHFR
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    indexed on : Thu Oct 12 16:20:15 CEST 2017

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