RBCC Red Blood Cell Collection

MTHFD1 (MTHFC, MTHFD) [Confidence: high (present in two of the MS resources)]
C-1-tetrahydrofolate synthase, cytoplasmic; C1-THF synthase; Methylenetetrahydrofolate dehydrogenase; 1.5.1.5; Methenyltetrahydrofolate cyclohydrolase; 3.5.4.9; Formyltetrahydrofolate synthetase; 6.3.4.3; C-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processed
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00218342
IPI00218342 methylenetetrahydrofolate dehydrogenase 1 methylenetetrahydrofolate dehydrogenase 1 membrane 1 8 n/a n/a 5 n/a 2 1 5 n/a n/a n/a n/a n/a n/a n/a n/a 6 13 12 cytoplasmic n/a found at its expected molecular weight found at molecular weight

UniProt P11586
ID C1TC_HUMAN Reviewed; 935 AA.
AC P11586; B2R5Y2; G3V2B8; Q86VC9; Q9BVP5;
DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 161.
DE RecName: Full=C-1-tetrahydrofolate synthase, cytoplasmic;
DE Short=C1-THF synthase;
DE Includes:
DE RecName: Full=Methylenetetrahydrofolate dehydrogenase;
DE EC=1.5.1.5;
DE Includes:
DE RecName: Full=Methenyltetrahydrofolate cyclohydrolase;
DE EC=3.5.4.9;
DE Includes:
DE RecName: Full=Formyltetrahydrofolate synthetase;
DE EC=6.3.4.3;
DE Contains:
DE RecName: Full=C-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processed;
GN Name=MTHFD1; Synonyms=MTHFC, MTHFD;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 2-31.
RC TISSUE=Liver;
RX PubMed=3053686;
RA Hum D.W., Bell A.W., Rozen R., Mackenzie R.E.;
RT "Primary structure of a human trifunctional enzyme. Isolation of a
RT cDNA encoding methylenetetrahydrofolate dehydrogenase-
RT methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate
RT synthetase.";
RL J. Biol. Chem. 263:15946-15950(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT GLN-653.
RC TISSUE=Amygdala;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12508121; DOI=10.1038/nature01348;
RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S.,
RA Sun H., Du H., Pepin K., Artiguenave F., Robert C., Cruaud C.,
RA Bruels T., Jaillon O., Friedlander L., Samson G., Brottier P.,
RA Cure S., Segurens B., Aniere F., Samain S., Crespeau H., Abbasi N.,
RA Aiach N., Boscus D., Dickhoff R., Dors M., Dubois I., Friedman C.,
RA Gouyvenoux M., James R., Madan A., Mairey-Estrada B., Mangenot S.,
RA Martins N., Menard M., Oztas S., Ratcliffe A., Shaffer T., Trask B.,
RA Vacherie B., Bellemere C., Belser C., Besnard-Gonnet M.,
RA Bartol-Mavel D., Boutard M., Briez-Silla S., Combette S.,
RA Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., Muselet D.,
RA Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., Trybou A.,
RA Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L.,
RA Verdier J., Verdier-Discala C., Hillier L.W., Fulton L., McPherson J.,
RA Matsuda F., Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W.,
RA Quetier F., Waterston R., Hood L., Weissenbach J.;
RT "The DNA sequence and analysis of human chromosome 14.";
RL Nature 421:601-607(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT GLN-653.
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS GLN-653 AND
RP PHE-769.
RC TISSUE=Brain, Eye, and Lymph;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP PROTEIN SEQUENCE OF 2-17.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [7]
RP PROTEIN SEQUENCE OF 2-17; 251-264; 314-324; 355-362; 596-616 AND
RP 722-733, CLEAVAGE OF INITIATOR METHIONINE, LACK OF N-TERMINAL
RP ACETYLATION, AND MASS SPECTROMETRY.
RC TISSUE=Foreskin fibroblast, and Prostatic carcinoma;
RA Bienvenut W.V., Gao M., Leug H., Campbell A., Ozanne B.W.;
RL Submitted (JUL-2009) to UniProtKB.
RN [8]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 1-302.
RX PubMed=9519408; DOI=10.1016/S0969-2126(98)00019-7;
RA Allaire M., Li Y., Mackenzie R.E., Cygler M.;
RT "The 3-D structure of a folate-dependent dehydrogenase/cyclohydrolase
RT bifunctional enzyme at 1.5-A resolution.";
RL Structure 6:173-182(1998).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 1-306 IN COMPLEX WITH NADP
RP AND SUBSTRATE ANALOGS, SUBUNIT, AND MUTAGENESIS OF SER-49; TYR-52;
RP LYS-56 AND CYS-147.
RX PubMed=10828945; DOI=10.1021/bi992734y;
RA Schmidt A., Wu H., MacKenzie R.E., Chen V.J., Bewly J.R., Ray J.E.,
RA Toth J.E., Cygler M.;
RT "Structures of three inhibitor complexes provide insight into the
RT reaction mechanism of the human methylenetetrahydrofolate
RT dehydrogenase/cyclohydrolase.";
RL Biochemistry 39:6325-6335(2000).
RN [13]
RP ASSOCIATION OF VARIANT HIS-293 WITH SUSCEPTIBILITY TO FS-NTD, AND
RP VARIANT GLN-653.
RX PubMed=9611072;
RA Hol F.A., van der Put N.M.J., Geurds M.P.A., Heil S.G.,
RA Trijbels F.J.M., Hamel B.C.J., Mariman E.C.M., Blom H.J.;
RT "Molecular genetic analysis of the gene encoding the trifunctional
RT enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase,
RT methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate
RT synthetase) in patients with neural tube defects.";
RL Clin. Genet. 53:119-125(1998).
RN [14]
RP ASSOCIATION OF VARIANT GLN-653 WITH SUSCEPTIBILITY TO FS-NTD, AND
RP VARIANT LYS-134.
RX PubMed=12384833; DOI=10.1086/344213;
RA Brody L.C., Conley M., Cox C., Kirke P.N., McKeever M.P., Mills J.L.,
RA Molloy A.M., O'Leary V.B., Parle-McDermott A., Scott J.M.,
RA Swanson D.A.;
RT "A polymorphism, R653Q, in the trifunctional enzyme
RT methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate
RT cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic
RT risk factor for neural tube defects: report of the Birth Defects
RT Research Group.";
RL Am. J. Hum. Genet. 71:1207-1215(2002).
RN [15]
RP ASSOCIATION OF VARIANT GLN-653 WITH SUSCEPTIBILITY TO FS-NTD, AND
RP VARIANT LYS-134.
RX PubMed=16552426; DOI=10.1038/sj.ejhg.5201603;
RA Parle-McDermott A., Kirke P.N., Mills J.L., Molloy A.M., Cox C.,
RA O'Leary V.B., Pangilinan F., Conley M., Cleary L., Brody L.C.,
RA Scott J.M.;
RT "Confirmation of the R653Q polymorphism of the trifunctional C1-
RT synthase enzyme as a maternal risk for neural tube defects in the
RT Irish population.";
RL Eur. J. Hum. Genet. 14:768-772(2006).
RN [16]
RP VARIANT LYS-134, AND ASSOCIATION WITH COLORECTAL CANCER
RP SUSCEPTIBILITY.
RX PubMed=17000706; DOI=10.1093/hmg/ddl401;
RA Webb E.L., Rudd M.F., Sellick G.S., El Galta R., Bethke L., Wood W.,
RA Fletcher O., Penegar S., Withey L., Qureshi M., Johnson N.,
RA Tomlinson I., Gray R., Peto J., Houlston R.S.;
RT "Search for low penetrance alleles for colorectal cancer through a
RT scan of 1467 non-synonymous SNPs in 2575 cases and 2707 controls with
RT validation by kin-cohort analysis of 14 704 first-degree relatives.";
RL Hum. Mol. Genet. 15:3263-3271(2006).
RN [17]
RP CHARACTERIZATION OF VARIANT GLN-653, AND ASSOCIATION WITH RISK OF
RP CONGENITAL HEART DEFECTS.
RX PubMed=18767138; DOI=10.1002/humu.20830;
RA Christensen K.E., Rohlicek C.V., Andelfinger G.U., Michaud J.,
RA Bigras J.-L., Richter A., Mackenzie R.E., Rozen R.;
RT "The MTHFD1 p.Arg653Gln variant alters enzyme function and increases
RT risk for congenital heart defects.";
RL Hum. Mutat. 30:212-220(2009).
CC -!- CATALYTIC ACTIVITY: 5,10-methylenetetrahydrofolate + NADP(+) =
CC 5,10-methenyltetrahydrofolate + NADPH.
CC -!- CATALYTIC ACTIVITY: 5,10-methenyltetrahydrofolate + H(2)O = 10-
CC formyltetrahydrofolate.
CC -!- CATALYTIC ACTIVITY: ATP + formate + tetrahydrofolate = ADP +
CC phosphate + 10-formyltetrahydrofolate.
CC -!- PATHWAY: One-carbon metabolism; tetrahydrofolate interconversion.
CC -!- SUBUNIT: Homodimer.
CC -!- INTERACTION:
CC P23508:MCC; NbExp=1; IntAct=EBI-709638, EBI-307531;
CC Q9Y4K3:TRAF6; NbExp=1; IntAct=EBI-709638, EBI-359276;
CC Q9P2S5:WDR8; NbExp=1; IntAct=EBI-709638, EBI-1054904;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- DOMAIN: This trifunctional enzyme consists of two major domains:
CC an N-terminal part containing the methylene-THF dehydrogenase and
CC cyclohydrolase activities and a larger C-terminal part containing
CC formyl-THF synthetase activity.
CC -!- DISEASE: Folate-sensitive neural tube defects (FS-NTD)
CC [MIM:601634]: The most common NTDs are open spina bifida
CC (myelomeningocele) and anencephaly. Note=Disease susceptibility is
CC associated with variations affecting the gene represented in this
CC entry.
CC -!- DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease
CC characterized by malignant lesions arising from the inner wall of
CC the large intestine (the colon) and the rectum. Genetic
CC alterations are often associated with progression from
CC premalignant lesion (adenoma) to invasive adenocarcinoma. Risk
CC factors for cancer of the colon and rectum include colon polyps,
CC long-standing ulcerative colitis, and genetic family history.
CC Note=Disease susceptibility may be associated with variations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: In the N-terminal section; belongs to the
CC tetrahydrofolate dehydrogenase/cyclohydrolase family.
CC -!- SIMILARITY: In the C-terminal section; belongs to the formate--
CC tetrahydrofolate ligase family.
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DR EMBL; J04031; AAA59574.1; -; mRNA.
DR EMBL; AK312361; BAG35279.1; -; mRNA.
DR EMBL; AL122035; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471061; EAW80857.1; -; Genomic_DNA.
DR EMBL; BC001014; AAH01014.2; -; mRNA.
DR EMBL; BC009806; AAH09806.1; -; mRNA.
DR EMBL; BC050420; AAH50420.1; -; mRNA.
DR PIR; A31903; A31903.
DR RefSeq; NP_005947.3; NM_005956.3.
DR UniGene; Hs.652308; -.
DR PDB; 1A4I; X-ray; 1.50 A; A/B=1-301.
DR PDB; 1DIA; X-ray; 2.20 A; A/B=1-306.
DR PDB; 1DIB; X-ray; 2.70 A; A/B=1-306.
DR PDB; 1DIG; X-ray; 2.20 A; A/B=1-306.
DR PDBsum; 1A4I; -.
DR PDBsum; 1DIA; -.
DR PDBsum; 1DIB; -.
DR PDBsum; 1DIG; -.
DR ProteinModelPortal; P11586; -.
DR SMR; P11586; 2-296, 317-935.
DR IntAct; P11586; 7.
DR MINT; MINT-5000922; -.
DR STRING; 9606.ENSP00000216605; -.
DR BindingDB; P11586; -.
DR ChEMBL; CHEMBL2541; -.
DR DrugBank; DB00157; NADH.
DR DrugBank; DB00116; Tetrahydrofolic acid.
DR PhosphoSite; P11586; -.
DR DMDM; 115206; -.
DR REPRODUCTION-2DPAGE; IPI00218342; -.
DR SWISS-2DPAGE; P11586; -.
DR PaxDb; P11586; -.
DR PRIDE; P11586; -.
DR DNASU; 4522; -.
DR Ensembl; ENST00000216605; ENSP00000216605; ENSG00000100714.
DR Ensembl; ENST00000555709; ENSP00000450560; ENSG00000100714.
DR GeneID; 4522; -.
DR KEGG; hsa:4522; -.
DR UCSC; uc001xhb.3; human.
DR CTD; 4522; -.
DR GeneCards; GC14P064854; -.
DR H-InvDB; HIX0011731; -.
DR HGNC; HGNC:7432; MTHFD1.
DR HPA; HPA000704; -.
DR HPA; HPA001290; -.
DR HPA; HPA015006; -.
DR MIM; 114500; phenotype.
DR MIM; 172460; gene+phenotype.
DR MIM; 601634; phenotype.
DR neXtProt; NX_P11586; -.
DR Orphanet; 268392; Cervical spina bifida aperta.
DR Orphanet; 268762; Cervical spina bifida cystica.
DR Orphanet; 268397; Cervicothoracic spina bifida aperta.
DR Orphanet; 268766; Cervicothoracic spina bifida cystica.
DR Orphanet; 268388; Lumbosacral spina bifida aperta.
DR Orphanet; 268758; Lumbosacral spina bifida cystica.
DR Orphanet; 268384; Thoracolumbosacral spina bifida aperta.
DR Orphanet; 268752; Thoracolumbosacral spina bifida cystica.
DR Orphanet; 268377; Total spina bifida aperta.
DR Orphanet; 268748; Total spina bifida cystica.
DR Orphanet; 268740; Upper thoracic spina bifida aperta.
DR Orphanet; 268770; Upper thoracic spina bifida cystica.
DR PharmGKB; PA31236; -.
DR eggNOG; COG0190; -.
DR HOVERGEN; HBG004916; -.
DR InParanoid; P11586; -.
DR KO; K00288; -.
DR BioCyc; MetaCyc:HS02138-MONOMER; -.
DR BRENDA; 6.3.4.3; 2681.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR UniPathway; UPA00193; -.
DR ChiTaRS; MTHFD1; human.
DR EvolutionaryTrace; P11586; -.
DR GeneWiki; MTHFD1; -.
DR GenomeRNAi; 4522; -.
DR NextBio; 17468; -.
DR PRO; PR:P11586; -.
DR ArrayExpress; P11586; -.
DR Bgee; P11586; -.
DR CleanEx; HS_MTHFD1; -.
DR Genevestigator; P11586; -.
DR GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR GO; GO:0005829; C:cytosol; IBA:RefGenome.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IEA:InterPro.
DR GO; GO:0004329; F:formate-tetrahydrofolate ligase activity; IEA:InterPro.
DR GO; GO:0004477; F:methenyltetrahydrofolate cyclohydrolase activity; IBA:RefGenome.
DR GO; GO:0004488; F:methylenetetrahydrofolate dehydrogenase (NADP+) activity; IEA:InterPro.
DR GO; GO:0004486; F:methylenetetrahydrofolate dehydrogenase [NAD(P)+] activity; TAS:Reactome.
DR GO; GO:0046655; P:folic acid metabolic process; TAS:Reactome.
DR GO; GO:0009396; P:folic acid-containing compound biosynthetic process; IEA:InterPro.
DR GO; GO:0000105; P:histidine biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0009086; P:methionine biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0006730; P:one-carbon metabolic process; IBA:RefGenome.
DR GO; GO:0006164; P:purine nucleotide biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0035999; P:tetrahydrofolate interconversion; IEA:UniProtKB-UniPathway.
DR Gene3D; 3.40.50.720; -; 1.
DR InterPro; IPR000559; Formate_THF_ligase.
DR InterPro; IPR020628; Formate_THF_ligase_CS.
DR InterPro; IPR016040; NAD(P)-bd_dom.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR000672; THF_DH/CycHdrlase.
DR InterPro; IPR020630; THF_DH/CycHdrlase_cat_dom.
DR InterPro; IPR020867; THF_DH/CycHdrlase_CS.
DR InterPro; IPR020631; THF_DH/CycHdrlase_NAD-bd_dom.
DR Pfam; PF01268; FTHFS; 1.
DR Pfam; PF00763; THF_DHG_CYH; 1.
DR Pfam; PF02882; THF_DHG_CYH_C; 1.
DR PRINTS; PR00085; THFDHDRGNASE.
DR SUPFAM; SSF52540; SSF52540; 2.
DR PROSITE; PS00721; FTHFS_1; 1.
DR PROSITE; PS00722; FTHFS_2; 1.
DR PROSITE; PS00766; THF_DHG_CYH_1; 1.
DR PROSITE; PS00767; THF_DHG_CYH_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Amino-acid biosynthesis; ATP-binding;
KW Complete proteome; Cytoplasm; Direct protein sequencing;
KW Disease mutation; Histidine biosynthesis; Hydrolase; Ligase;
KW Methionine biosynthesis; Multifunctional enzyme; NADP;
KW Nucleotide-binding; One-carbon metabolism; Oxidoreductase;
KW Polymorphism; Purine biosynthesis; Reference proteome.
FT CHAIN 1 935 C-1-tetrahydrofolate synthase,
FT cytoplasmic.
FT /FTId=PRO_0000423280.
FT INIT_MET 1 1 Removed; alternate.
FT CHAIN 2 935 C-1-tetrahydrofolate synthase,
FT cytoplasmic, N-terminally processed.
FT /FTId=PRO_0000199321.
FT NP_BIND 172 174 NADP.
FT NP_BIND 380 387 ATP (By similarity).
FT REGION 2 305 Methylenetetrahydrofolate dehydrogenase
FT and cyclohydrolase.
FT REGION 52 56 Substrate binding.
FT REGION 99 101 Substrate binding.
FT REGION 272 276 Substrate binding.
FT REGION 306 935 Formyltetrahydrofolate synthetase.
FT BINDING 197 197 NADP.
FT SITE 2 2 Not acetylated.
FT MOD_RES 1 1 N-acetylmethionine.
FT VARIANT 134 134 R -> K (associated with increased risk of
FT colorectal cancer; dbSNP:rs1950902).
FT /FTId=VAR_016232.
FT VARIANT 162 162 P -> L (in dbSNP:rs4902283).
FT /FTId=VAR_055458.
FT VARIANT 293 293 R -> H (associated with susceptibility to
FT FS-NTD; dbSNP:rs34181110).
FT /FTId=VAR_010241.
FT VARIANT 653 653 R -> Q (may be associated with
FT susceptibility to FS-NTD; decreases
FT enzyme stability and increases risk for
FT congenital heart defects;
FT dbSNP:rs2236225).
FT /FTId=VAR_010251.
FT VARIANT 761 761 T -> M (in dbSNP:rs10813).
FT /FTId=VAR_032789.
FT VARIANT 769 769 L -> F (in dbSNP:rs17857382).
FT /FTId=VAR_032790.
FT MUTAGEN 49 49 S->A: No effect on dehydrogenase and
FT cyclohydrolase activity. Strong increase
FT of Km for NADP.
FT MUTAGEN 49 49 S->Q: Reduces dehydrogenase by 75% and
FT cyclohydrolase activity by 99%. No effect
FT on Km for NADP and for 5,10-
FT methenyltetrahydrofolate.
FT MUTAGEN 52 52 Y->A,S: Reduces dehydrogenase activity by
FT 99%. Reduces cyclohydrolase activity by
FT 70%. No effect on Km for NADP and for
FT 5,10-methenyltetrahydrofolate.
FT MUTAGEN 52 52 Y->F: Slightly reduces dehydrogenase and
FT cyclohydrolase activity. Increase of Km
FT for NADP and for 5,10-
FT methenyltetrahydrofolate.
FT MUTAGEN 56 56 K->A,I,S,T: Decreases dehydrogenase
FT activity over 90%. Loss of cyclohydrolase
FT activity.
FT MUTAGEN 56 56 K->E,M,Q: Moderate decrease of
FT dehydrogenase activity. Loss of
FT cyclohydrolase activity. Strong increase
FT of Km for NADP. Decrease of Km for 5,10-
FT methenyltetrahydrofolate.
FT MUTAGEN 56 56 K->R: Reduces dehydrogenase and
FT cyclohydrolase activity by 99%. No effect
FT on Km for NADP and for 5,10-
FT methenyltetrahydrofolate.
FT MUTAGEN 147 147 C->Q: Reduces dehydrogenase activity by
FT 50% and cyclohydrolase activity by 87%.
FT HELIX 9 30
FT STRAND 37 44
FT HELIX 47 63
FT STRAND 66 72
FT HELIX 78 90
FT STRAND 96 99
FT HELIX 111 116
FT HELIX 120 122
FT HELIX 129 136
FT HELIX 147 157
FT TURN 158 160
FT STRAND 167 171
FT TURN 175 177
FT HELIX 178 187
FT STRAND 191 195
FT HELIX 202 206
FT STRAND 210 214
FT HELIX 224 226
FT STRAND 232 235
FT HELIX 258 261
FT TURN 262 264
FT STRAND 266 268
FT STRAND 271 274
FT HELIX 275 295
SQ SEQUENCE 935 AA; 101559 MW; 29AE1C04B4922885 CRC64;
MAPAEILNGK EISAQIRARL KNQVTQLKEQ VPGFTPRLAI LQVGNRDDSN LYINVKLKAA
EEIGIKATHI KLPRTTTESE VMKYITSLNE DSTVHGFLVQ LPLDSENSIN TEEVINAIAP
EKDVDGLTSI NAGRLARGDL NDCFIPCTPK GCLELIKETG VPIAGRHAVV VGRSKIVGAP
MHDLLLWNNA TVTTCHSKTA HLDEEVNKGD ILVVATGQPE MVKGEWIKPG AIVIDCGINY
VPDDKKPNGR KVVGDVAYDE AKERASFITP VPGGVGPMTV AMLMQSTVES AKRFLEKFKP
GKWMIQYNNL NLKTPVPSDI DISRSCKPKP IGKLAREIGL LSEEVELYGE TKAKVLLSAL
ERLKHRPDGK YVVVTGITPT PLGEGKSTTT IGLVQALGAH LYQNVFACVR QPSQGPTFGI
KGGAAGGGYS QVIPMEEFNL HLTGDIHAIT AANNLVAAAI DARIFHELTQ TDKALFNRLV
PSVNGVRRFS DIQIRRLKRL GIEKTDPTTL TDEEINRFAR LDIDPETITW QRVLDTNDRF
LRKITIGQAP TEKGHTRTAQ FDISVASEIM AVLALTTSLE DMRERLGKMV VASSKKGEPV
SAEDLGVSGA LTVLMKDAIK PNLMQTLEGT PVFVHAGPFA NIAHGNSSII ADRIALKLVG
PEGFVVTEAG FGADIGMEKF FNIKCRYSGL CPHVVVLVAT VRALKMHGGG PTVTAGLPLP
KAYIQENLEL VEKGFSNLKK QIENARMFGI PVVVAVNAFK TDTESELDLI SRLSREHGAF
DAVKCTHWAE GGKGALALAQ AVQRAAQAPS SFQLLYDLKL PVEDKIRIIA QKIYGADDIE
LLPEAQHKAE VYTKQGFGNL PICMAKTHLS LSHNPEQKGV PTGFILPIRD IRASVGAGFL
YPLVGTMSTM PGLPTRPCFY DIDLDPETEQ VNGLF
//

MIM 114500
*RECORD*
*FIELD* NO
114500
*FIELD* TI
#114500 COLORECTAL CANCER; CRC
;;COLON CANCER
*FIELD* TX
A number sign (#) is used with this entry because mutations in several
read moredifferent genes have been identified in colorectal cancer (CRC).

DESCRIPTION

Colorectal cancer is a heterogeneous disease that is common in both men
and women. In addition to lifestyle and environmental risk factors, gene
defects can contribute to an inherited predisposition to CRC. CRC is
caused by changes in different molecular pathogenic pathways, such as
chromosomal instability, CpG island methylator phenotype, and
microsatellite instability. Chromosome instability is the most common
alteration and is present in almost 85% of all cases (review by
Schweiger et al., 2013).

- Genetic Heterogeneity of Colorectal Cancer

Mutations in a single gene result in a marked predisposition to
colorectal cancer in 2 distinct syndromes: familial adenomatous
polyposis (FAP; 175100) and hereditary nonpolyposis colorectal cancer
(HNPCC; see 120435). FAP is caused by mutations in the APC gene
(611731), whereas HNPCC is caused by mutations in several genes,
including MSH2 (609309), MLH1 (120436), PMS1 (600258), PMS2 (600259),
MSH6 (600678), TGFBR2 (190182), and MLH3 (604395). Epigenetic silencing
of MSH2 results in a form of HNPCC (see HNPCC8, 613244). Other
colorectal cancer syndromes include autosomal recessive adenomatous
polyposis (608456), which is caused by mutations in the MUTYH gene
(604933), and oligodontia-colorectal cancer syndrome (608615), which is
caused by mutations in the AXIN2 gene (604025).

The CHEK2 gene (604373) has been implicated in susceptibility to
colorectal cancer in Finnish patients. A germline mutation in the
PLA2G2A gene (172411) was identified in a patient with colorectal
cancer.

Germline susceptibility loci for colorectal cancer have also been
identified. CRCS1 (608812) is conferred by mutation in the GALNT12 gene
(610290) on chromosome 9q22; CRCS2 (611469) maps to chromosome 8q24;
CRCS3 (612229) is conferred by variation in the SMAD7 gene (602932) on
chromosome 18; CRCS4 (601228) is conferred by variation on 15q that
causes increased and ectopic expression of the GREM1 gene (603054);
CRCS5 (612230) maps to chromosome 10p14; CRCS6 (612231) maps to
chromosome 8q23; CRCS7 (612232) maps to chromosome 11q23; CRCS8 (612589)
maps to chromosome 14q22; CRCS9 (612590) maps to 16q22; CRCS10 (612591)
is conferred by mutation in the POLD1 gene (174761) on chromosome 19q13;
CRCS11 (612592) maps to chromosome 20p12; and CRCS12 (615083) is
conferred by mutation in the POLE gene (174762) on chromosome 12q24.

Somatic mutations in many different genes, including KRAS (190070),
PIK3CA (171834), BRAF (164757), CTNNB1 (116806), FGFR3 (134934), AXIN2
(604025), AKT1 (164730), MCC (159350), MYH11 (160745), and PARK2
(602544) have been identified in colorectal cancer.

CLINICAL FEATURES

Colon cancer is a well-known feature of familial polyposis coli. Cancer
of the colon occurred in 7 members of 4 successive generations of the
family reported by Kluge (1964), leading him to suggest a simple genetic
basis for colonic cancer independent of polyposis. The combination of
colonic and endometrial cancer has been observed in many families (e.g.,
Williams, 1978).

Sivak et al. (1981) studied a kindred with the familial cancer syndrome
in which every confirmed affected member had at least 1 primary
carcinoma of the colon. The average age at which cancer appeared was 38
years. Multiple primary neoplasms occurred in 23% of cancer patients.

Budd and Fink (1981) reported a family with a high frequency of mucoid
colonic carcinoma. Since endometrial carcinoma, atypical endometrial
hyperplasia, uterine leiomyosarcoma, bladder transitional carcinoma, and
renal cell carcinoma also occurred in the family, this may be the same
disorder as the Lynch cancer family syndrome type II (120435).

Bamezai et al. (1984) reported an Indian Sikh kindred in which 8 persons
suffered from cancer of the cecum, not associated with polyposis.

Burt et al. (1985) studied a large Utah kindred called to attention
because of occurrence of colorectal cancer in a brother, a sister, and a
nephew. No clear inheritance pattern was discernible until systematic
screening was undertaken for colonic polyps using flexible
proctosigmoidoscopy. One or more adenomatous polyps were found in 41 of
191 family members (21%) and 12 of 132 controls (9%)--p less than 0.005.
Pedigree analysis showed best fit with autosomal dominant inheritance.
Cannon-Albright et al. (1988) extended the studies with investigations
of 33 additional kindreds. The kindreds were selected through either a
single person with an adenomatous polyp or a cluster of relatives with
colonic cancer. The kindreds all had common colorectal cancers, not the
rare inherited condition of familial polyposis coli or nonpolyposis
inherited colorectal cancer. Likelihood analysis strongly supported
dominant inheritance of a susceptibility to colorectal adenomas and
cancers, with a gene frequency of 19%. According to the most likely
genetic model, adenomatous polyps and colorectal cancers occur only in
genetically susceptible persons; however, the 95% confidence interval
for this proportion was 53 to 100%.

Ponz de Leon et al. (1992) analyzed data on 605 families of probands
with colorectal cancer in the province of Modena in Italy. Among the 577
presumed nonpolyposis cases, both parents had colorectal cancer in 11,
one parent in 130, and neither parent in 436. Segregation was compatible
with dominant transmission of susceptibility to cancer.

Mecklin (1987) investigated the frequency of hereditary colorectal
cancer among all colorectal cancer patients diagnosed in 1 Finnish
county during the 1970s. The cancer family syndrome type of hereditary
nonpolyposis colorectal carcinoma emerged as the most common verifiable
risk factor, involving between 3.8 and 5.5% of all colorectal cancer
patients. The frequencies of familial adenomatosis and ulcerative
colitis were 0.2% and 0.6%, respectively. The observed frequency is
probably an underestimate. The patients with cancer family syndrome were
young, accounting for 29 to 39% of the patients under 50 years of age,
and their tumors were located predominantly (65%) in the right
hemicolon.

PATHOGENESIS

The state of DNA methylation appears to play a role in genetic
instability in colorectal cancer cells. Lengauer et al. (1997) noted
that DNA methylation is essential in prokaryotes, dispensable in lower
eukaryotes (such as Saccharomyces cerevisiae) yet present and presumably
important in mammals. Many cancers have been shown to have a global
hypomethylation of DNA compared with normal tissues. Treatment of cells
or animals with 5-azacytidine (5-aza-C), a demethylating agent that
irreversibly inactivates methyltransferase (see 156569), is oncogenic in
vitro and in vivo. Conversely, other studies showed that
hypermethylation of specific sequences found in some tumors can be
associated with the inactivation of tumor suppressor gene expression.
Mice genetically deficient in methyltransferase are resistant to
colorectal tumorigenesis initiated by mutation of the APC (611731) tumor
suppressor gene, and treatment of these mice with 5-aza-C enhances the
resistance (Laird et al., 1995).

Lengauer et al. (1997) reported a striking difference in the expression
of exogenously introduced retroviral genes in various colorectal cancer
cell lines. Extinguished expression was associated with DNA methylation
and could be reversed by treatment with the demethylating agent 5-aza-C.
A striking correlation between genetic instability and methylation
capacity suggested that methylation abnormalities may play a role in the
chromosome segregation processes in cancer cells. It has been speculated
that genetic instability is necessary for a tumor to accumulate the
numerous genetic alterations that accompany carcinogenesis. There
appeared to exist 2 pathways of genetic instability in colorectal
cancer. The first is found in about 15% of tumors and involves point
mutations, microdeletions, and microinsertions associated with
deficiency of mismatch repair (MMR). The second is found in
MMR-proficient cells and involves gains and losses of whole chromosomes.
Lengauer et al. (1997) suggested that methylation abnormalities are
intrinsically and directly involved in the generation of the second type
of instability, thus allowing for the selection of methylation-negative
cells during the clonal evolution of tumors. The hypothesis was
supported by the observation that demethylation is associated with
chromosomal aberrations, including mitotic dysfunction and
translocation, and was consistent with the hypothesis relating
methylation and aneuploidy put forward by Thomas (1995). Jones and
Gonzalgo (1997) commented on altered DNA methylation and genome
instability as a new pathway to cancer.

In a second report, Lengauer et al. (1997) showed that tumors without
microsatellite instability exhibit a striking defect in chromosome
segregation, resulting in gains or losses in excess of 10(-2) per
chromosome per generation. This form of chromosomal instability
reflected a continuing cellular defect that persisted throughout the
lifetime of the tumor cell and was not simply related to chromosome
number. While microsatellite instability is a recessive trait,
chromosomal instability appeared to be dominant. The data indicated that
persistent genetic instability may be critical for the development of
all colorectal cancers, and that this instability can arise through 2
distinct pathways.

Adenocarcinoma of the small intestine is rare in the general population,
but its histologic features are similar to those of the much more common
colorectal adenocarcinoma, and it is seen as part of the HNPCC tumor
predisposition spectrum. Wheeler et al. (2002) examined the possible
role of mismatch repair defects in the pathogenesis of sporadic small
intestinal adenocarcinoma. The replication error status was determined
in a total of 21 nonfamilial, nonampullary small intestinal
adenocarcinomas: only 1 tumor was scored as replication error-positive.
This tumor showed normal immunostaining for MLH1 (see 120436) and MSH2.
The authors commented that this result may reflect an epigenetic change
in the tumor rather than germline mutation in a mismatch repair gene,
and concluded that mismatch repair defects were unlikely to contribute
significantly to the genetic pathway leading to sporadic small
intestinal adenocarcinoma.

Vilar and Gruber (2010) reviewed the role of microsatellite instability
(MSI) in the development of CRC. They stated that approximately 15% of
CRCs display MSI owing either to epigenetic silencing of MLH1 or to a
germline mutation in one of the mismatch repair genes MLH1, MSH2, MSH6,
or PMS2. They noted that MSI tumors have a better prognosis than
microsatellite stable CRCs, but that MSI cancers do not necessarily have
the same response to the chemotherapeutic strategies used to treat
microsatellite stable tumors.

Batlle et al. (2005) showed that although Wnt (see 164820) signaling
remains constitutively active, most human colorectal cancers lose
expression of EphB (see 600600) at the adenoma-carcinoma transition.
They found that loss of EphB expression strongly correlated with degree
of malignancy. Furthermore, reduction of EphB activity accelerated
tumorigenesis in the colon and rectum of Apc(Min/+) mice (see 611731),
and resulted in formation of aggressive adenocarcinomas. Batlle et al.
(2005) concluded that loss of EphB expression represents a critical step
in colorectal cancer progression.

By microdissection of bifurcating colonic crypts and sequencing of the
entire mitochondrial genome in all of the cells, Greaves et al. (2006)
demonstrated that stochastic mutations in mtDNA resulting in phenotypic
cytochrome c oxidase (COX) deficiency of were identical in both arms of
a crypt that was bifurcating. Furthermore, they showed that patches of
neighboring crypts deficient in COX also shared identical mitochondrial
mutations, and that these patches increased in size with age, indicating
that crypt fission is a mechanism by which mutations can spread within
the colon.

Xia et al. (2012) showed that prostaglandin E2 (PGE2) silences certain
tumor suppressor and DNA repair genes through DNA methylation to promote
tumor growth. Their findings uncovered a theretofore unrecognized role
for PGE2 in the promotion of tumor progression, and provided a rationale
for considering the development of a combination treatment using PTGS2
(600262) inhibitors and demethylating agents for the prevention or
treatment of colorectal cancer.

Seshagiri et al. (2012) systematically analyzed more than 70 pairs of
primary human colon tumors using next-generation sequencing to
characterize their exomes, transcriptomes, and copy number alterations.
They identified 36,303 protein-altering somatic changes that included
several novel recurrent mutations in the Wnt pathway gene TCF7L2
(602228), chromatin-remodeling genes such as TET2 (612839) and TET3
(613555), and receptor tyrosine kinases including ERBB3 (190151). The
analysis for significantly mutated cancer genes identified 23
candidates, including the cell cycle checkpoint kinase ATM (607585).
Copy number and RNA-seq data analysis identified amplifications and
corresponding overexpression of IGF2 in a subset of colon tumors.
Furthermore, using RNA-seq data, Seshagiri et al. (2012) identified
multiple fusion transcripts including recurrent gene fusions involving
R-spondin family members RSPO2 (610575) and RSPO3 (610574) that together
occur in 10% of colon tumors. The RSPO fusions were mutually exclusive
with APC (611731) mutations, indicating that they probably have a role
in the activation of Wnt signaling and tumorigenesis. Consistent with
this, Seshagiri et al. (2012) showed that RSPO fusion proteins were
capable of potentiating Wnt signaling.

Grivennikov et al. (2012) investigated mechanisms responsible for
tumor-elicited inflammation in a mouse model of colorectal tumorigenesis
which, like human colorectal cancer, exhibits upregulation of IL23
(605580) and IL17 (603149). They showed that IL23 signaling promotes
tumor growth and progression, and development of tumoral IL17 response.
IL23 is mainly produced by tumor-associated myeloid cells that are
likely to be activated by microbial products, which penetrate the tumors
but not adjacent tissue. Both early and late colorectal neoplasms
exhibit defective expression of several barrier proteins. Grivennikov et
al. (2012) proposed that barrier deterioration induced by colorectal
cancer-initiating genetic lesions results in adenoma invasion by
microbial products that trigger tumor-elicited inflammation, which in
turn drives tumor growth.

Huber et al. (2012) described the crucial role of IL22BP (606648) in
controlling tumorigenesis and epithelial cell proliferation in the
colon. IL22BP is highly expressed by dendritic cells in the colon in
steady-state conditions. Sensing of intestinal tissue damage via the
NLRP3 (606416) or NLRP6 (609650) inflammasomes led to an IL18
(600953)-dependent downregulation of IL22BP, thereby increasing the
ratio of IL22 (605330)/IL22BP. IL22, which is induced during intestinal
tissue damage, exerted protective properties during the peak of damage,
but promoted tumor development if uncontrolled during the recovery
phase. Thus, the IL22-IL22BP axis critically regulates intestinal tissue
repair and tumorigenesis in the colon.

Vermeulen et al. (2013) quantified the competitive advantage during
tumor development of Apc (611731) loss, Kras (190070) activation, and
p53 (191170) mutations in the mouse intestine. Their findings indicated
that the fate conferred by these mutations is not deterministic, and
many mutated stem cells are replaced by wildtype stem cells after biased
but still stochastic events. Furthermore, Vermeulen et al. (2013) found
that p53 mutations display a condition-dependent advantage, and
especially in colitis-affected intestines, clones harboring mutations in
this gene were favored. Vermeulen et al. (2013) concluded that their
work confirmed the notion that the tissue architecture of the intestine
suppresses the accumulation of mutated lineages.

CLINICAL MANAGEMENT

Various laboratory, clinical, and epidemiologic evidence suggested that
calcium may help prevent colorectal adenomas. Baron et al. (1999)
conducted a randomized, double-blind trial of the effect of
supplementation with calcium carbonate on the recurrence of colorectal
adenomas. They found a significant, though moderate, reduction in the
risk of recurrent colorectal adenomas in the supplemented group.

In randomized trials of aspirin to determine its efficacy in prevention
of colorectal adenomas, Sandler et al. (2003) and Baron et al. (2003)
studied patients with either previous colorectal cancer or recent
histologically documented adenomas, respectively. Both studies found
that aspirin was associated with a significant reduction in the
incidence of colorectal adenomas.

Inhibition of the BRAF(V600E) (164757.0001) oncoprotein by the
small-molecule drug PLX4032 (vemurafenib) is highly effective in the
treatment of melanoma. However, colon cancer patients harboring the same
BRAF(V600E) oncogenic lesion have poor prognosis and show only a very
limited response to this drug. To investigate the cause of this limited
therapeutic effect in BRAF(V600E) mutant colon cancer, Prahallad et al.
(2012) performed an RNA interference-based genetic screen in human cells
to search for kinases whose knockdown synergizes with BRAF(V600E)
inhibition. They reported that blockade of the epidermal growth factor
receptor (EGFR; 131550) shows strong synergy with BRAF(V600E)
inhibition. Prahallad et al. (2012) found in multiple BRAF(V600E) mutant
colon cancers that inhibition of EGFR by the antibody drug cetuximab or
the small-molecule drugs gefitinib or erlotinib is strongly synergistic
with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically,
Prahallad et al. (2012) found that BRAF(V600E) inhibition causes a rapid
feedback activation of EGFR, which supports continued proliferation in
the presence of BRAF(V600E) inhibition. Melanoma cells express low
levels of EGFR and are therefore not subject to this feedback
activation. Consistent with this, Prahallad et al. (2012) found that
ectopic expression of EGFR in melanoma cells is sufficient to cause
resistance to PLX4032. Prahallad et al. (2012) concluded that
BRAF(V600E) mutant colon cancers (approximately 8 to 10% of all colon
cancers) might benefit from combination therapy consisting of BRAF and
EGFR inhibitors.

- Development of Resistance to Chemotherapeutic Agents

Antibodies against EGFR, cetuximab and panitumumab, are widely used to
treat colorectal cancer. Unfortunately, patients eventually develop
resistance to these agents. Montagut et al. (2012) described an acquired
EGFR ectodomain mutation (S492R) that prevents cetuximab binding and
confers resistance to cetuximab. Cells with this mutation, however,
retain binding to and are growth inhibited by panitumumab. Two of 10
subjects studied with metastatic colon cancer progression after
cetuximab treatment acquired this mutation. One subject with cetuximab
resistance harboring the S492R mutation responded to treatment with
panitumumab.

Misale et al. (2012) showed that molecular alterations (in most
instances point mutations) of KRAS (190070) are causally associated with
the onset of acquired resistance to anti-EGFR treatment in colorectal
cancers. Expression of mutant KRAS under the control of its endogenous
gene promoter was sufficient to confer cetuximab resistance, but
resistant cells remained sensitive to combinatorial inhibition of EGFR
and mitogen-activated protein kinase kinase (MEK; see 176872). Analysis
of metastases from patients who developed resistance to cetuximab or
panitumumab showed the emergence of KRAS amplification in one sample and
acquisition of secondary KRAS mutations in 60% (6 out of 10) of the
cases. KRAS mutant alleles were detectable in the blood of
cetuximab-treated patients as early as 10 months before radiographic
documentation of disease progression. Misale et al. (2012) concluded
that their results identified KRAS mutations as frequent drivers of
acquired resistance to cetuximab in colorectal cancers, indicated that
the emergence of KRAS mutant clones can be detected noninvasively months
before radiographic progression, and suggested early initiation of a MEK
inhibitor as a rational strategy for delaying or reversing drug
resistance.

Diaz et al. (2012) determined whether mutant KRAS DNA could be detected
in the circulation of 28 patients receiving monotherapy with
panitumumab, a therapeutic anti-EGFR antibody. They found that 9 out of
24 (38%) patients whose tumors were initially KRAS wildtype developed
detectable mutations in KRAS in their sera, 3 of which developed
multiple different KRAS mutations. The appearance of these mutations was
very consistent, generally occurring between 5 and 6 months following
treatment. Mathematical modeling indicated that the mutations were
present in expanded subclones before the initiation of panitumumab
treatment. Diaz et al. (2012) concluded that the emergence of KRAS
mutations is a mediator of acquired resistance to EGFR blockade and that
these mutations can be detected in a noninvasive manner. The results
also explained why solid tumors develop resistance to targeted therapies
in a highly reproducible fashion.

Among 512 patients who had metastatic colorectal cancer without RAS
(KRAS or NRAS, 164790) mutations, Douillard et al. (2013) found that
progression-free survival was 10.1 months with the combination of
panitumumab-FOLFOX4 (oxaliplatin, fluorouracil, and leucovorin) versus
7.9 months with FOLFOX4 alone (hazard ratio for progression or death
with combination therapy, 0.72; 95% CI 0.58 to 0.90; p = 0.004). Overall
survival was 26.0 months in the panitumumab-FOLFOX4 group versus 20.2
months in the FOLFOX4-alone group (hazard ratio for death, 0.78; 95% CI
0.62-0.99; p = 0.04). A total of 108 patients (17%) with nonmutated KRAS
exon 2 had other RAS mutations. These mutations were associated with
inferior progression-free survival and overall survival with
panitumumab-FOLFOX4 treatment, which was consistent with the findings in
patients with KRAS mutations in exon 2. BRAF mutations were a negative
prognostic factor.

DIAGNOSIS

- Prediction of Colorectal Cancer Risk

Loss of imprinting, an epigenetic alteration affecting the insulin-like
growth factor II gene (IGF2; 147470), is found in normal colonic mucosa
of about 30% of colorectal cancer patients, but it is found in only 10%
of healthy individuals. In a pilot study to investigate the utility of
loss of imprinting as a marker of colorectal cancer risk, Cui et al.
(2003) evaluated 172 patients at a colonoscopy clinic. The adjusted odds
ratio for loss of imprinting in lymphocytes was 5.15 for patients with a
positive family history (95% CI, 1.70-16.96; p = 0.002), 3.46 for
patients with adenomas (95% CI, 1.14-11.37; p = 0.026), and 21.7 for
patients with colorectal cancer (95% CI, 3.48-153.6; p = 0.0005). Loss
of imprinting can be assayed with a DNA-based blood test, and Cui et al.
(2003) concluded that it may be a valuable predictive marker of an
individual's risk for colorectal cancer.

MAPPING

To identify susceptibility genes for familial colorectal neoplasia,
Daley et al. (2008) conducted a comprehensive, genomewide linkage scan
of 194 kindreds. Clinical information (histopathology, size and number
of polyps, and other primary cancers) was used in conjunction with age
at onset and family history for classification of the families into 5
phenotypic subgroups (severe histopathology, oligopolyposis, young
colon/breast and multiple cancer) before analysis. By expanding the
traditional affected sib pair design to include unaffected and
discordant sib pairs, analytical power and robustness to type I error
were increased. Linkage peaks of interest were identified at several
sites. At marker D1S1665 (1p31.1), there was strong evidence for linkage
in the multiple cancer subgroup (p = 0.00007). For 15q14-q22, a linkage
peak was identified in the full sample, oligopolyposis, and young
phenotypes. This region includes the locus associated with hereditary
mixed polyposis syndrome (HMPS; 601228) in families of Ashkenazi
descent. Daley et al. (2008) provided compelling evidence linking this
region in families of European descent with oligopolyposis and/or young
age at onset (51 years or younger) phenotypes. They found linkage to
BRCA2 (600185) in the colon/breast phenotypic subgroup and identified a
second locus in the region of D21S1437 segregating with, but distinct
from, BRCA2. Linkage to 17p13.3 at marker D17S1308 in the breast/colon
subgroup identified HIC1 (603825) as a candidate gene. The study
demonstrated that using clinical information, unaffected sibs, and
family history can increase the analytic power of a linkage study.

- Associations Pending Confirmation

In a large kindred with excess colorectal cancer, Neklason et al. (2010)
performed 2 separate genomewide scans and additional fine mapping and
identified a single major locus on chromosome 13q22.1-q31.3 that
segregated with adenomatous polyps and colon cancer, for which they
obtained a nonparametric linkage score of 24 (lod score of 2.99; p =
0.001) at D13S251. Haplotype analysis identified a 21-Mb interval
encompassing a nonrecombinant region bounded by dbSNP rs2077779 and
dbSNP rs2351871 and containing 27 genes. Sequencing of 8 candidate genes
failed to identify a clearly deleterious mutation. Neklason et al.
(2010) noted that chromosome 13q is commonly gained and overexpressed in
colon cancers and correlates with metastasis, suggesting the presence of
an important cancer progression gene, and stated that evaluation of
tumors from the kindred revealed a gain of chromosome 13q as well.

CYTOGENETICS

Bass et al. (2011) reported whole-genome sequencing from 9 individuals
with colorectal cancer, including primary colorectal tumors and matched
adjacent nontumor tissues, at an average of 30.7x and 31.9x coverage,
respectively. They identified an average of 75 somatic rearrangements
per tumor, including complex networks of translocations between pairs of
chromosomes. Eleven rearrangements encode predicted in-frame fusion
proteins, including a fusion of VTI1A (614316) and TCF7L2 (602278) found
in 3 out of 97 colorectal cancers. Although TCF7L2 encodes TCF4, which
cooperates with beta-catenin (116806) in colorectal carcinogenesis, the
fusion lacks the TCF4 beta-catenin-binding domain. Bass et al. (2011)
found a colorectal carcinoma cell line harboring the fusion gene to be
dependent on VTI1A-TCF7L2 for anchorage-independent growth using RNA
interference-mediated knockdown.

MOLECULAR GENETICS

In the DNA from 1 colon and 2 lung carcinoma cell lines, Perucho et al.
(1981) demonstrated the same or closely related transforming elements.
By DNA-mediated gene transfer, mouse fibroblasts could be
morphologically transformed and rendered tumorigenic in nude mice.

In preliminary observations, Pathak and Goodacre (1986) found deletion
of 12p in colorectal cancer specimens.

Fearon et al. (1987) studied the clonal composition of human colorectal
tumors. Using X-linked RFLPs, they showed that all 50 tumors from
females showed a monoclonal pattern of X-chromosome inactivation; these
tumors included 20 carcinomas and 30 adenomas of either familial or
spontaneous type. In over 75% of carcinomas examined, somatic loss of
chromosome 17p sequences was found; such loss was rare in adenomas.
Fearon et al. (1987) suggested that a gene on the short arm of
chromosome 17 may be associated with progression from the benign to the
malignant state.

By a combination of DNA hybridization analyses and tissue sectioning
techniques, Bos et al. (1987) demonstrated that RAS gene mutations occur
in over a third of colorectal cancers, that most of the mutations are at
codon 12 of the KRAS gene (190070), and that the mutations usually
precede the development of malignancy.

In 38 tumors from 25 patients with familial polyposis coli, and in 20
sporadic colon carcinomas, Okamoto et al. (1988) found frequent
occurrence of allele loss on chromosome 22, with some additional losses
on chromosomes 5, 6, 12q, and 15. The DNA probe C11p11, which has been
found to be linked to familial polyposis coli, also detected frequent
allele loss in both familial and sporadic colon carcinomas but not in
benign adenomas. In a more extensive study, Vogelstein et al. (1988)
studied the interrelationships of the 4 alterations demonstrated in
colorectal cancer (RAS gene mutations and deletions of chromosome 5, 17
and 18 sequences) and determined their occurrence with respect to
different stages of colorectal tumorigenesis. They found RAS gene
mutations frequently in adenomas, this being the first demonstration of
such in benign human tumors. In adenomas greater than 1 cm in size, the
prevalence was similar to that observed in carcinomas (58% and 47%,
respectively). Sequences on chromosome 5 that are linked to familial
adenomatous polyposis were seldom lost in adenomas from such patients.
Therefore, the Knudson model is unlikely to be applicable to the
adenoma/carcinoma sequence in this disorder. Chromosome 18 sequences
were lost frequently in colon carcinomas (73%) and in advanced adenomas
(47%), but only occasionally in earlier stage adenomas (11-13%); see
120470. Chromosome 17 sequences were usually lost only in carcinomas
(75%). The results suggested a model wherein the steps required for
malignancy involve the activation of a dominantly acting oncogene
coupled with the loss of several genes that normally suppress
tumorigenesis.

Wildrick and Boman (1988) found deletion of the glucocorticoid receptor
locus (138040), located on 5q, in colorectal cancers.

Law et al. (1988) examined the question of whether the gene for familial
polyposis coli on chromosome 5 may be the site of changes leading to
colorectal cancer in the general population, analogous to recessive
tumor genes in retinoblastoma and Wilms tumor. To avoid error in
interpretation of allelic loss from a study of nonhomogeneous samples,
tumor cell populations were first microdissected from 24 colorectal
carcinomas, an additional 9 cancers were engrafted in nude mice, and
nuclei were flow-sorted in an additional 2. Of 31 cancers informative
for chromosome 5 markers, only 6 (19%) showed loss of heterozygosity of
chromosome 5 alleles, compared to 19 of 34 (56%) on chromosome 17, and
17 of 33 (52%) on chromosome 18. Law et al. (1988) concluded that FPC is
a true dominant for adenomatosis but not a common recessive gene for
colon cancer, and that simple mendelian models involving loss of alleles
at a single locus may be inappropriate for understanding common human
solid tumors.

Vogelstein et al. (1989) examined the extent and variation of allelic
loss for polymorphic DNA markers in every nonacrocentric autosomal arm
in 56 paired colorectal carcinoma and adjacent normal colonic mucosa
specimens. They referred to the analysis as an allelotype, in analogy
with a karyotype. Three major conclusions were drawn from the study: (1)
Allelic deletions are remarkably common; 1 of the alleles of each
polymorphic marker tested was lost in at least some tumors, and some
tumors lost more than half of their parental alleles. (2) In addition to
allelic deletions, new DNA fragments not present in normal tissue were
identified in 5 carcinomas; these new fragments contained repeated
sequences (of the variable-number-of-tandem-repeat type). (3) Patients
with more than the median percentage of allelic deletions had a
considerably worse prognosis than did the other patients, although the
stage and size of the primary tumors were very similar in the 2 groups.

Delattre et al. (1989) reviewed the 3 general types of genetic
alterations in colorectal cancer: (1) change in DNA content of the
malignant cells as monitored by flow cytometry; (2) specific loss of
genetic material, i.e., a complete loss of chromosome 18 and a
structural rearrangement of chromosome 17 leading most often to the loss
of 1 short arm, and loss of part of 5q as demonstrated by loss of
heterozygosity; and (3) in nearly 40% of tumors, activation by point
mutation of RAS oncogenes (never HRAS, rarely NRAS, and most frequently
KRAS). In KRAS, with 1 exception, the activation has always occurred by
a change in the coding properties of the twelfth or thirteenth codon. In
studies of the multiple genetic alterations in colorectal cancer,
Delattre et al. (1989) found that deletions and mitotic abnormalities
occurred more frequently in distal than in proximal tumors. The
frequency of KRAS mutations did not differ between proximal and distal
cancers.

In studies of 15 colorectal tumors, Konstantinova et al. (1991) found
rearrangements of the short arm of chromosome 17, leading to deletion of
this arm or part of it in 12; in 2 others, one of the homologs of pair
17 was lost. One chromosome 18 was lost in 12 out of 13 cases with fully
identified numerical abnormalities; chromosome 5, in 6 tumors; and other
chromosomes in lesser numbers of cases. See 120470 for a discussion of a
gene on chromosome 18 called DCC ('deleted in colorectal cancer') that
shows mutations, including point mutations, in colorectal tumor tissue;
also see 164790 for a discussion of a mutation in the NRAS oncogene in
colorectal cancer.

On the basis of complex segregation analysis of a published series of
consecutive pedigrees ascertained through patients undergoing treatment
for colorectal cancer, Houlston et al. (1992) concluded that a dominant
gene (or genes) with a frequency of 0.006 with a lifetime penetrance of
0.63 is likely. The gene was thought to account for 81% of colorectal
cancer in patients under 35 years of age; however, by age 65, about 85%
appeared to be phenocopies.

Fearon and Vogelstein (1990) reviewed the evidence supporting their
multistep genetic model for colorectal tumorigenesis. They suggested
that multiple mutations lead to a progression from normal epithelium to
metastatic carcinoma through hyperplastic epithelium--early
adenoma--intermediate adenoma--late adenoma--and carcinoma. The genes in
which mutations occur at steps in this process include APC (611731) on
chromosome 5, KRAS on chromosome 12, TP53 (191170) on 17p, and DCC on
chromosome 18. Other genes that have been demonstrated or suspected of
involvement in colorectal cancer include MSH2 (609309) on chromosome 2
and the DRA candidate colon tumor-suppressor gene (126650) on chromosome
7. Sarraf et al. (1999) presented evidence that colon cancer in humans
is associated with loss-of-function mutations in the PPARG gene
(601487).

Kikuchi-Yanoshita et al. (1992) presented evidence that genetic changes
in both alleles of the TP53 gene through mutation and LOH, which result
in abnormal protein accumulation, are involved in the conversion of
adenoma to early carcinoma in both familial adenomatous polyposis and in
nonfamilial polyposis cases.

Kinzler and Vogelstein (1996) gave a review of hereditary colorectal
cancer and the multistep process of carcinogenesis that typically
develops over decades and appears to require at least 7 genetic events
for completion. They stated that the genetic defect in FAP involves the
rate of tumor initiation by targeting the gatekeeper function of the APC
gene. In contrast, the defect in HNPCC largely affects tumor aggression
by targeting the genome guardian function of DNA repair.

Rajagopalan et al. (2002) systematically evaluated mutation in BRAF
(164757) and KRAS (190070) in 330 colorectal tumors. There were 32
mutations in BRAF, 28 with a V600E mutation (164757.0001) and 1 each
with the R462I (164757.0002), I463S (164757.0003), G464E (164757.0004),
or K601E (164757.0005) mutations. All but 2 mutations seemed to be
heterozygous, and in all 20 cases for which normal tissue was available,
the mutations were shown to be somatic. In the same set of tumors there
were 169 mutations in KRAS. No tumor exhibited mutations in both BRAF
and KRAS. There was also a striking difference in the frequency of BRAF
mutations between cancers with and without mismatch repair deficiency.
All but 1 of the 15 BRAF mutations identified in mismatch repair
deficient cases resulted in a V600E substitution. Rajagopalan et al.
(2002) concluded their results provide strong support for the hypothesis
that BRAF and KRAS mutations are equivalent in their tumorigenic
effects. Both genes seem to be mutated at a similar phase of
tumorigenesis, after initiation but before malignant conversion.
Moreover, no tumor concurrently contained both BRAF and KRAS mutations.

To determine whether carriers of BLM (604610) mutations are at increased
risk of colorectal cancer, Gruber et al. (2002) genotyped 1,244 cases of
colorectal cancer and 1,839 controls, both of Ashkenazi Jewish ancestry,
to estimate the relative risk of colorectal cancer among carriers of the
BLM(Ash) founder mutation. Ashkenazi Jews with colorectal cancer were
more than twice as likely to carry the BLM(Ash) (604610.0001) mutation
than Ashkenazi Jewish controls without colorectal cancer (odds ratio =
2.45, 95% confidence interval 1.3 to 4.8; p = 0.0065). Gruber et al.
(2002) verified that the APC I1307K mutation (611731.0029) did not
confound their results.

Lynch and de la Chapelle (2003) provided a general discussion of
hereditary colorectal cancer. They presented a flow diagram of the
breakdown of 1,044 unselected consecutive patients with colorectal
cancer. Tumors from 129 patients (12%) were positive for microsatellite
instability; 28 of these patients were positive for germline mutations
in MLH1 or MSH2, giving HNPCC a 2.7% frequency among the 1,044 patients.
In the 88% of the patients whose tumors had no microsatellite
instability, no mutations were found in MLH1 or MSH2.

Bardelli et al. (2003) used high-throughput sequencing technologies and
bioinformatics to investigate how many or how often members of the
tyrosine kinase family were altered in any particular cancer type. The
protein kinase complement of the human genome (the 'kinome') can be
organized into a dendrogram containing 9 broad groups of genes. Bardelli
et al. (2003) selected 1 major branch of this dendrogram, containing 3
of the 9 groups, including the 90 tyrosine kinase genes (TK group), the
43 tyrosine kinase-like genes (TKL group), and the 5 receptor guanylate
cyclase genes (RGC group), for mutation analysis. The 819 exons
containing the kinase domains from the annotated TK, TKL, and RGC genes
were screened from 35 colorectal cancer cell lines and were directly
sequenced. Fourteen genes had somatic mutations within their kinase
domains. Bardelli et al. (2003) analyzed these 14 genes for mutations in
another 147 colorectal cancers and identified 46 mutations, 2 of which
were synonymous; the remainder were either nonsynonymous or splice site
alterations. All of these mutations were found to be somatic in the
cancers that could be assessed by sequencing DNA from matched normal
tissue. Seven genes were mutated in more than 1 tumor in the cohort:
NTRK3 (191316), FES (190030), KDR (191306), EPHA3 (179611), NTRK2
(600456), MLK4, and GUCY2F (300041).

Samuels et al. (2004) examined the sequences of 117 exons that encode
the predicted kinase domains of 8 phosphatidylinositol-3 kinase genes
and 8 PI3K-like genes in 35 colorectal cancers. PIK3CA (171834) was the
only gene with somatic mutations. Subsequent sequence analysis of all
coding exons of PIK3CA in 199 additional colorectal cancers revealed
mutations in a total of 74 tumors (32%). Samuels et al. (2004) also
evaluated 76 premalignant colorectal tumors; only 2 mutations were
found, both in very advanced tubulovillous adenomas greater than 5 cm in
diameter. Thus, Samuels et al. (2004) concluded that PIK3CA mutations
generally arise late in tumorigenesis, just before or coincident with
invasion. Mutations in PIK3CA were also identified in 4 of 15
glioblastomas (27%), 3 of 12 gastric cancers (25%), 1 of 12 breast
cancers (8%), and 1 of 24 lung cancers (4%). No mutations were observed
in 11 pancreatic cancers or 12 medulloblastomas. In total, 92 mutations
were observed, all of which were determined to be somatic in the cancers
that could be assessed. Samuels et al. (2004) concluded that the sheer
number of mutations observed in this gene strongly suggests that they
are functionally important. Furthermore, most of the mutations were
nonsynonymous and occurred in the PI3K helical and kinase domains,
suggesting functional significance.

Clear-cut inherited mendelian traits, such as FAP or HNPCC, account for
less than 4% of colorectal cancers. Another 20% of all colorectal
cancers are thought to occur in individuals with a significant inherited
multifactorial susceptibility to colorectal cancer that is not obviously
familial. Incompletely penetrant, comparatively rare missense variants
in the APC gene (611731) have been described in patients with multiple
colorectal adenomas. For example, the I1307K mutation in the APC gene,
which is found in Ashkenazi Jewish populations with an incidence of
approximately 6%, confers a significantly increased risk of developing
multiple adenomas and colorectal cancer. The glu1317-to-gln mutation in
the APC gene (E1317Q; 611731.0036), which is found in non-Jewish
Caucasian populations at a low frequency, similarly appears to confer a
significantly increased risk of multiple adenomatous polyps. These
variants represent a category of variation that has been suggested,
generally, to account for a substantial fraction of such multifactorial
inherited susceptibility to colorectal cancer. Fearnhead et al. (2004)
explored this rare variant hypothesis for multifactorial inheritance
using multiple colorectal adenomas as the model. Patients with multiple
adenomas were screened for germline variants in a panel of candidate
genes. Germline DNA was obtained from 124 patients with 3 to 100
histologically proven synchronous or metachronous adenomatous polyps.
All patients were tested for the APC gene variants I1307K and E1317Q and
for variants in the AXIN1 (603816), CTNNB1, MLH1, and MSH2 genes. The
control group consisted of 483 randomly selected individuals.
Potentially pathogenic germline variants were found in 30 of 124
patients (24.9%), compared with 55 of 483 controls (approximately 12%).
This overall difference was highly significant, suggesting that many
rare variants collectively contribute to inherited susceptibility to
colorectal adenomas.

Parsons et al. (2005) selected 340 genes encoding serine/threonine
kinases from the human genome and analyzed them for mutations in the
kinase domain in tumors from colorectal cancer patients. A total of 23
changes, including 20 nonsynonymous point mutations, 1 insertion, and 1
splice site alteration, were identified. The gene mutations affected 8
different proteins: 6 were in mitogen-activated protein kinase kinase-4
(MKK4/JNKK1; 601335), 6 in myosin light-chain kinase-2 (MYLK2; 606566),
3 in phosphoinositide-dependent protein kinase-1 (PDK1; 605213, of which
2 mutations affected the same residue in the kinase domain), 2 in
p21-activated kinase-4 (PAK4; 605451), 2 in v-akt murine thymoma viral
oncogene homolog-2 kinase (AKT2; 164731), and 2 in MAP/microtubule
affinity-regulating kinase-3 (MARK3; 602678); there was 1 alteration in
cell-division cycle-7 kinase (CDC7; 603311) and another in a
hypothetical casein kinase (PDIK1L). Eighteen of the 23 somatic
mutations occurred at evolutionarily conserved residues. MKK4/JNKK1 is
altered in a variety of tumor types, but no mutations in any of the
other genes had theretofore been found in colorectal cancers. Three of
the altered genes, PDK1, AKT2, and PAK4, encode proteins involved in the
phosphatidylinositol-3-hydroxykinase pathway, and 2 of these (AKT2 and
PAK4) are overexpressed in human cancers. Overall, nearly 40% of
colorectal tumors had alterations in 1 of 8 PI(3)K-pathway genes.

Boraska Jelavic et al. (2006) studied genotype and allele frequencies of
the GT microsatellite repeat polymorphism in intron 2 of the TLR2 gene
(603028.0002) in 89 Croatian patients with sporadic colorectal cancer
and 88 Croatian sex- and age-matched controls. The frequency of TLR2
alleles with 20 and 21 GT repeats was decreased (p = 0.0044 and p =
0.001, respectively) and the frequency of the allele with 31 GT repeats
was increased (p = 0.0147) in patients versus controls. The authors also
found that the gly299 allele of the TLR4 gene (603030.0001) was more
frequent in colorectal cancer patients than controls (p = 0.0269).

Sjoblom et al. (2006) determined the sequence of well-annotated human
protein-coding genes in 2 common tumor types. Analysis of 13,023 genes
in 11 breast and 11 colorectal cancers revealed that individual tumors
accumulate an average of about 90 mutant genes, but that only a subset
of these contribute to the neoplastic process. Using stringent criteria
to delineate this subset, Sjoblom et al. (2006) identified 189 genes
(average of 11 per tumor) that were mutated at significant frequency.
The vast majority of these were not known to be genetically altered in
tumors and were predicted to affect a wide range of cellular functions,
including transcription, adhesion, and invasion. Sjoblom et al. (2006)
concluded that their data defined the genetic landscape of 2 human
cancer types, provided new targets for diagnostic and therapeutic
intervention, and opened fertile avenues for basic research in tumor
biology.

Forrest and Cavet (2007), Getz et al. (2007), and Rubin and Green (2007)
commented on the article by Sjoblom et al. (2006), citing statistical
problems that, if addressed, would result in the identification of far
fewer genes with significantly elevated mutation rates. Parmigiani et
al. (2007) responded that the conclusions of the above authors were
inaccurate because they were based on analyses that did not fully take
into account the experimental design and other critical features of the
Sjoblom et al. (2006) study.

To catalog the genetic changes that occur during tumorigenesis, Wood et
al. (2007) isolated DNA from 11 breast and 11 colorectal tumors and
determined the sequences of the genes in the Reference Sequence database
in these samples. Based on analysis of exons representing 20,857
transcripts from 18,191 genes, Wood et al. (2007) concluded that the
genomic landscapes of breast and colorectal cancers are composed of a
handful of commonly mutated gene 'mountains' and a much larger number of
gene 'hills' that are mutated at low frequency. Wood et al. (2007)
described statistical and bioinformatic tools that may help identify
mutations with a role in tumorigenesis. The gene mountains are comprised
of well-known cancer genes such as APC (611731), KRAS (190070), and TP53
(191170). Furthermore, Wood et al. (2007) observed that most tumors
accumulated approximately 80 mutations, and that the majority of these
were harmless. Fewer than 15 mutations are likely to be responsible for
driving the initiation, progression, or maintenance of the tumor.

Alhopuro et al. (2008) identified somatic mutations in the MYH11 gene in
56 (56%) of 101 samples of colorectal cancer tissue showing
microsatellite instability. All 56 mutations were within a
mononucleotide repeat of 8 cytosines (C8) in the last exon of the MYH11
SM2 isoform, which is susceptible to mutations under microsatellite
instability, and were predicted to lead to a frameshift and elongation
of the protein. All mutations were found within epithelial cells.
Analysis of microsatellite stable tumors identified 2 somatic mutations
in the same tumor that were not in the C8 repeat. Functional expression
studies of the mutant proteins showed unregulated actin-activated motor
activity.

McMurray et al. (2008) showed that a large proportion of genes
controlled synergistically by loss-of-function p53 and Ras activation
are critical to the malignant state of murine and human colon cells.
Notably, 14 of 24 'cooperation response genes' were found to contribute
to tumor formation in gene perturbation experiments. In contrast, only 1
of 14 perturbations of the genes responding in a nonsynergistic manner
had a similar effect. McMurray et al. (2008) concluded that synergistic
control of gene expression by oncogenic mutations thus emerges as an
underlying key to malignancy, and provides an attractive rationale for
identifying intervention targets in gene networks downstream of
oncogenic gain- and loss-of-function mutations.

To help distinguish between driver and passenger mutations in colorectal
cancer, Starr et al. (2009) used a transposon-based genetic screen in
mice to identify candidate genes. Mice harboring mutagenic 'Sleeping
Beauty' (SB) transposons were crossed with mice expressing SB
transposase in gastrointestinal tract epithelium. Most of the offspring
developed intestinal lesions including intraepithelial neoplasia,
adenomas, and adenocarcinomas. Analysis of over 16,000 transposon
insertions identified 77 candidate CRC genes, 60 of which are mutated
and/or dysregulated in human CRC and thus are most likely to drive
tumorigenesis. The genes included APC, PTEN (601728), and SMAD4
(600993). The screen also identified 17 candidate genes that had not
been implicated in CRC, including POLI (605252), PTPRK (602545), and
RSPO2 (610575).

In colonocytes from COX-deficient crypts from 2 patients with colon
cancer, Greaves et al. (2006) identified 2 missense mutations in the
MTCO1 gene (see 516030.0010 and 516030.0011, respectively).

Using high-throughput screening of 14,662 human protein coding
transcripts, Sjoblom et al. (2006) found that the PKHD1 gene (606702)
was the seventh most common somatically mutated gene in colorectal
cancer. Germline mutations in the PKHD1 gene cause autosomal recessive
polycystic kidney disease (263200). Ward et al. (2011) observed an
association between the common T36M PKHD1 allele (606702.0001) and
protection against colorectal cancer. Germline heterozygosity for the
mutant allele was found in 0.42% of 3,603 healthy European controls and
in 0.027% of 3,767 patients with colorectal cancer (p = 0.0002; odds
ratio of 0.072). The authors postulated that reduced PKHD1 activity may
enhance mitotic instability, which may inhibit carcinogenesis.

Dorard et al. (2011) identified a mutant of HSP110 (see 610703), which
they called HSP110-delta-E9, in colorectal cancer showing microsatellite
instability (MSI CRC), generated from an aberrantly spliced mRNA and
lacking the HSP110 substrate-binding domain. This mutant was expressed
at variable levels in almost all MSI CRC cell lines and primary tumors
tested. HSP110-delta-E9 impaired both the normal cellular localization
of HSP110 and its interaction with other HSPs, thus abrogating the
chaperone activity and antiapoptotic function of HSP110 in a
dominant-negative manner. HSP110-delta-E9 overexpression caused the
sensitization of cells to anticancer agents such as oxaliplatin and
5-fluorouracil, which are routinely prescribed in the adjuvant treatment
of people with colorectal cancer. The survival and response to
chemotherapy of subjects with colorectal cancer showing microsatellite
instability was associated with the tumor expression level of
HSP110-delta-E9. Dorard et al. (2011) concluded that HSP110 may thus
constitute a major determinant for both prognosis and treatment response
in colorectal cancer.

The Cancer Genome Atlas Network (2012) conducted a genome-scale analysis
of 276 colorectal carcinoma samples analyzing exome sequence, DNA copy
number, promoter methylation, and mRNA and microRNA expression. A subset
of these samples (97) underwent low-depth-of-coverage whole-genome
sequencing. In total, 16% of colorectal carcinomas were found to be
hypermutated: three-quarters of these had the expected high
microsatellite instability, usually with hypermethylation and MLH1
silencing, and one-quarter had somatic mismatch-repair gene and
polymerase epsilon mutations. Excluding the hypermutated cancers, colon
and rectal cancers were found to have considerably similar patterns of
genomic alteration. Twenty-four genes were significantly mutated. In
addition to the expected APC, TP53, SMAD4, PIK3CA, and KRAS mutations,
the authors found frequent mutations in ARID1A (603024), SOX9 (608160),
and FAM123B (300647). Recurrent copy number alterations included
potentially drug-targetable amplification of ERBB2 (164870) and
amplification of IGF2 (147470). Recurrent chromosomal translocations
included the fusion of NAV2 (607026) and WNT pathway member TCF7L1
(604652). Integrative analyses suggested new markers for aggressive
colorectal carcinoma and an important role for MYC-directed
transcriptional activation and repression.

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46. Montagut, C.; Dalmases, A.; Bellosillo, B.; Crespo, M.; Pairet,
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54. Prahallad, A.; Sun, C.; Huang, S.; Di Nicolantonio, F.; Salazar,
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224-226, 2012.

*FIELD* CS

Oncology:
Hereditary nonpolyposis colorectal carcinoma;
Associated endometrial carcinoma, atypical endometrial hyperplasia,
uterine leiomyosarcoma, bladder transitional carcinoma, gastric, biliary
and renal cell carcinoma;
APC, RAS, DCC or KRAS gene mutations;
Allele loss on chromosomes 5, 6, 12q, 15, 17, 18, or 22

Inheritance:
Autosomal dominantly acting oncogene plus loss of suppressor gene(s)

*FIELD* CN
Ada Hamosh - updated: 12/06/2013
Ada Hamosh - updated: 10/23/2013
Cassandra L. Kniffin - updated: 2/18/2013
Ada Hamosh - updated: 12/4/2012
Ada Hamosh - updated: 9/18/2012
Ada Hamosh - updated: 9/5/2012
Ada Hamosh - updated: 8/10/2012
Ada Hamosh - updated: 7/17/2012
Ada Hamosh - updated: 6/26/2012
Ada Hamosh - updated: 3/15/2012
Ada Hamosh - updated: 3/14/2012
Ada Hamosh - updated: 12/12/2011
Cassandra L. Kniffin - updated: 4/20/2011
Marla J. F. O'Neill - updated: 12/1/2010
Carol A. Bocchini - updated: 11/4/2010
Marla J. F. O'Neill - updated: 10/5/2009
Ada Hamosh - updated: 9/14/2009
Ada Hamosh - updated: 6/18/2009
Ada Hamosh - updated: 7/29/2008
Ada Hamosh - updated: 7/18/2008
Cassandra L. Kniffin - updated: 4/28/2008
Ada Hamosh - updated: 2/14/2008
Ada Hamosh - updated: 1/9/2008
Victor A. McKusick - updated: 11/20/2007
Ada Hamosh - updated: 10/31/2006
Marla J. F. O'Neill - updated: 9/22/2006
Ada Hamosh - updated: 9/8/2005
Ada Hamosh - updated: 7/27/2005
Victor A. McKusick - updated: 4/15/2005
Ada Hamosh - updated: 4/30/2004
Ada Hamosh - updated: 5/29/2003
Ada Hamosh - updated: 4/3/2003
Victor A. McKusick - updated: 3/14/2003
Ada Hamosh - updated: 9/30/2002
George E. Tiller - updated: 9/26/2002
Ada Hamosh - updated: 9/17/2002
Paul Brennan - updated: 3/19/2002
Paul Brennan - updated: 3/13/2002
Paul Brennan - updated: 3/6/2002
George E. Tiller - updated: 6/19/2001
Stylianos E. Antonarakis - updated: 7/20/1999
Victor A. McKusick - updated: 2/9/1999
Victor A. McKusick - updated: 4/21/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
alopez: 12/06/2013
alopez: 10/23/2013
tpirozzi: 10/1/2013
carol: 3/11/2013
carol: 2/19/2013
ckniffin: 2/18/2013
alopez: 12/6/2012
terry: 12/4/2012
alopez: 9/19/2012
terry: 9/18/2012
alopez: 9/5/2012
carol: 8/10/2012
terry: 8/10/2012
terry: 7/27/2012
alopez: 7/19/2012
terry: 7/17/2012
alopez: 6/26/2012
terry: 6/26/2012
alopez: 3/15/2012
alopez: 3/14/2012
alopez: 12/19/2011
terry: 12/12/2011
carol: 9/7/2011
wwang: 5/2/2011
ckniffin: 4/20/2011
carol: 4/20/2011
wwang: 12/3/2010
carol: 12/2/2010
terry: 12/1/2010
carol: 11/4/2010
carol: 3/19/2010
alopez: 2/4/2010
ckniffin: 1/15/2010
wwang: 10/14/2009
terry: 10/5/2009
wwang: 9/29/2009
alopez: 9/14/2009
wwang: 7/29/2009
alopez: 6/24/2009
terry: 6/18/2009
wwang: 2/13/2009
ckniffin: 2/9/2009
terry: 1/12/2009
terry: 1/9/2009
carol: 9/19/2008
alopez: 8/18/2008
terry: 7/29/2008
wwang: 7/18/2008
wwang: 6/9/2008
ckniffin: 4/28/2008
carol: 2/15/2008
alopez: 2/15/2008
terry: 2/14/2008
ckniffin: 2/5/2008
carol: 1/31/2008
ckniffin: 1/28/2008
alopez: 1/28/2008
terry: 1/9/2008
alopez: 12/7/2007
terry: 11/20/2007
alopez: 9/27/2007
alopez: 8/31/2007
alopez: 11/3/2006
terry: 10/31/2006
alopez: 10/9/2006
wwang: 9/22/2006
wwang: 5/17/2006
carol: 4/14/2006
alopez: 12/5/2005
alopez: 9/9/2005
terry: 9/8/2005
alopez: 7/28/2005
terry: 7/27/2005
carol: 6/3/2005
mgross: 4/15/2005
mgross: 4/14/2005
mgross: 4/13/2005
tkritzer: 2/11/2005
alopez: 4/30/2004
terry: 4/30/2004
carol: 7/10/2003
mgross: 5/29/2003
joanna: 5/29/2003
terry: 5/29/2003
terry: 4/3/2003
carol: 3/21/2003
tkritzer: 3/18/2003
terry: 3/14/2003
alopez: 9/30/2002
tkritzer: 9/30/2002
cwells: 9/26/2002
alopez: 9/17/2002
alopez: 3/19/2002
alopez: 3/13/2002
alopez: 3/6/2002
cwells: 6/20/2001
cwells: 6/19/2001
carol: 10/20/2000
carol: 8/12/1999
mgross: 7/20/1999
mgross: 2/16/1999
mgross: 2/15/1999
terry: 2/9/1999
alopez: 6/27/1997
jenny: 4/21/1997
terry: 4/14/1997
terry: 12/10/1996
terry: 12/9/1996
carol: 5/31/1994
terry: 5/13/1994
mimadm: 4/9/1994
warfield: 4/6/1994
carol: 2/24/1993
carol: 10/12/1992

MIM 172460
*RECORD*
*FIELD* NO
172460
*FIELD* TI
*172460 METHYLENETETRAHYDROFOLATE DEHYDROGENASE 1; MTHFD1
;;METHYLENETETRAHYDROFOLATE DEHYDROGENASE/METHENYLTETRAHYDROFOLATE CYCLOHYDROLASE/FORMYLTETRAHYDROFOLATE
read moreSYNTHETASE, NADP(+)-DEPENDENT;;
CYCLOHYDROLASE/FORMYLTETRAHYDROFOLATE SYNTHETASE, NADP(+)-DEPENDENT;;
C1-TETRAHYDROFOLATE SYNTHASE, CYTOPLASMIC;;
C1-THF-SYNTHASE
*FIELD* TX

DESCRIPTION

The MTHFD1 gene encodes a trifunctional protein comprising
5,10-methylenetetrahydrofolate dehydrogenase (EC 1.5.1.5),
5,10-methenyltetrahydrofolate cyclohydrolase (EC 3.5.4.9), and
10-formyltetrahydrofolate synthetase (EC 6.3.4.3). These 3 sequential
reactions are involved in the interconversion of 1-carbon derivatives of
tetrahydrofolate (THF) which are substrates for methionine, thymidylate,
and de novo purine syntheses. In eukaryotes, the 3 enzymatic activities
are properties of a single protein, a homodimer of 100-kD polypeptides.
The eukaryotic trifunctional enzyme consists of 2 major domains, an
N-terminal containing the dehydrogenase and cyclohydrolase activities
and a larger synthetase domain in the C terminus (Hum et al., 1988).

See also MTHFD2 (604887).

CLONING

Hum et al. (1988) isolated a cDNA clone corresponding to the human
trifunctional MTHFD1 gene from a human liver cDNA library. The deduced
935-amino acid protein has a molecular mass of approximately 101 kD. The
10-formyltetrahydrofolate synthetase activity is found in the C-terminal
domain. Northern blot analysis identified a 3.1-kb mRNA transcript.

MAPPING

By somatic cell hybridization and in situ hybridization, Rozen et al.
(1989) mapped the MTHFD1 gene to chromosome 14q24.

- Pseudogene

Italiano et al. (1991) demonstrated that the MTHFD sequence located on
the X chromosome (Xp11) is an intronless pseudogene.

MOLECULAR GENETICS

Women who take folic acid periconceptionally can substantially reduce
their risk of having a child with a neural tube defect (NTD; 601634).
Hol et al. (1998) identified a mutation in the MTHFD1 gene (R293H;
172460.0001) in 1 of 38 unrelated patients with familial NTD. The
mutation was present in 3 unaffected family members and in none of 79
sporadic cases. Hol et al. (1998) concluded that mutations in the MTHFD1
gene may act as a risk factor for NTD.

Brody et al. (2002) analyzed 5 potential single-nucleotide polymorphisms
(SNPs) in the MTHFD1 gene for an association with NTDs in the Irish
population. One SNP, R653Q (172460.0002), appeared to be associated with
NTD risk. They observed an excess of the MTHFD1 Q allele in the mothers
of children with NTD, compared with control individuals. This excess was
driven by the overrepresentation of QQ homozygotes in the mothers of
children with NTD, compared with control individuals (odds ratio, 1.52;
p = 0.003). They concluded that genetic variation in the MTHFD1 gene is
associated with an increase in the genetically determined risk that a
woman will bear a child with NTD and that the gene may be associated
with decreased embryo survival.

De Marco et al. (2006) also reported an association between the R653Q
polymorphism and neural tube defects in an Italian population.

Van der Linden et al. (2007) did not find an association between the
R653Q polymorphism and spina bifida among 103 Dutch patients and their
mothers.

HISTORY

Kao and Puck (1972) found that hybrids formed from an adenine-requiring
Chinese hamster cell and human fibroblasts uniformly displayed new
esterase activity. Hybrids that grew in selective medium showed a single
extra chromosome resembling a B-group human chromosome. They postulated
a human activator gene, designated esterase activator (ESAT), linked to
the ade B gene, located on a B-group chromosome and capable of
activating the mouse locus.

Functional complementation of mutations in the yeast Saccharomyces
cerevisiae and Chinese hamster ovary cells resulting in an inability to
synthesize adenine (Ade-) led to the identification of human genes
involved in de novo purine biosynthesis. Two of these genes were
identified as phosphoribosylglycinamide formyltransferase (GART; 138440)
and phosphoribosyl formylglycinamide synthetase (PFAS; 602133),
corresponding to Ade-E and Ade-B, respectively (Patterson, 1986). The
human gene that complemented the defects was originally assigned to
chromosome 14q22-qter, according to the findings of somatic cell hybrid
studies (Kao, 1980; Kao and Puck, 1972; Jones et al., 1981; Kao et al.,
1984). However, it is now known that the gene locus mapped to 14q is not
GART or PFAS, but rather the MTHFD1 gene encoding enzymatic synthesis of
the folate cofactor required by both enzymes. Henikoff et al. (1986)
showed by direct assay of extracts of mutant cells that GART levels were
normal, whereas levels of 5,10-methenyltetrahydrofolate cyclohydrolase
were greatly decreased.

Schild et al. (1990) isolated a human cDNA clone complementing the yeast
mutation Ade-3 (formyltetrahydrofolate synthetase). However, the cDNA
clone was distinct by size and by restriction map criteria from that of
the MTHFD1 clone reported by Hum et al. (1988) and was found instead to
represent the MTHFD2 gene (604887).

Barton et al. (1991) gave a useful summary of the 12 enzymatic steps
involved in the biosynthetic pathway for the production of AMP from
phosphoribosylpyrophosphate (PRPP) as well as the 1-carbon cycle that
supplies 1-carbon units for purine synthesis with 5 enzymes. The Ade(-)E
mutation lies in the latter cycle, whereas the Ade(-)B mutation is at
the fourth step in the pathway from PRPP to AMP. The enzymes involved
have been mapped to 7 different chromosomes.

Human deficiency of the cyclohydrolase activity was proposed by Arakawa
et al. (1966), but Arakawa (1970) later stated the uncertainty of this
as a distinct entity.

*FIELD* AV
.0001
SPINA BIFIDA, FOLATE-SENSITIVE, SUSCEPTIBILITY TO
MTHFD1, ARG293HIS

In a boy with spina bifida (601634), Hol et al. (1998) identified a
heterozygous 878G-A transition in the MTHFD1 gene, resulting in an
arg293-to-his (R293H) substitution. The mutation was transmitted from
the healthy maternal grandmother to the healthy mother and was also
passed on to 2 other brothers, one with spina bifida occulta and the
other asymptomatic. The mutation was not observed in 300 control
samples. Hol et al. (1998) noted that the R293H substitution occurs in
the putative interdomain region of the protein between the enzymatic
regions and thus is not likely to affect enzymatic function, but may
alter the structural integrity of the protein. The investigators could
not evaluate the role of this mutation on plasma homocysteine
concentrations.

.0002
NEURAL TUBE DEFECTS, FOLATE-SENSITIVE, SUSCEPTIBILITY TO
MTHFD1, ARG653GLN

Hol et al. (1998) identified a 1958G-A transition in the MTHFD1 gene,
resulting in an arg653-to-gln (R653Q; dbSNP rs2236225) substitution. The
change was determined to be a polymorphism.

Brody et al. (2002) studied the R653Q polymorphism in the MTHFD1 gene in
the Irish population and found an overrepresentation of QQ homozygotes
in the mothers of children with neural tube defects (601634) compared
with control individuals.

De Marco et al. (2006) genotyped the MTHFD1 1958G-A polymorphism in 142
Italian children with NTD, 125 mothers, 108 fathers, and 523 controls.
An increased risk was found for the heterozygous 1958G/A and homozygous
1958A/A genotypes in the children (OR, 1.69 and 1.91, respectively). The
risk of an NTD-affected pregnancy was increased 1.67-fold only when a
dominant effect (1958G/A or A/A vs G/G) was analyzed. A significant
excess of transmission of the 1958A allele to affected individuals was
demonstrated. De Marco et al. (2006) concluded that heterozygosity and
homozygosity for the MTHFD1 1958G-A polymorphism are genetic
determinants of NTD risk in the Italian population.

Parle-McDermott et al. (2006) analyzed the MTHFD1 gene in an independent
sample of 245 Irish mothers with a history of NDT-affected pregnancy and
770 controls and found a significant excess of 1958AA homozygote mothers
of NTD cases compared to controls (OR, 1.49; p = 0.019). Parle-McDermott
et al. (2006) concluded that the 1958G-A polymorphism has a significant
role in influencing a mother's risk of having an NTD-affected pregnancy
in the Irish population.

Van der Linden et al. (2007) did not find an association between the
R653Q polymorphism and spina bifida among 103 Dutch patients and their
mothers.

Parle-McDermott et al. (2005) genotyped 62 women with severe abruptio
placentae and 184 control pregnancies and found an increased frequency
of the QQ homozygote genotype in the abruptio placentae pregnancies
compared to controls (OR, 2.85; p = 0.002). The authors concluded that
women who are QQ homozygotes for the MTHFD1 polymorphism are almost 3
times more likely to develop severe abruptio placentae than women who
are RQ or RR. Zdoukopoulos and Zintzaras (2008) performed a metaanalysis
of genetic risk factors for placental abruption, including the R653Q
substitution.

*FIELD* RF
1. Arakawa, T.: Congenital defects in folate utilization. Am. J.
Med. 48: 594-598, 1970.

2. Arakawa, T.; Fujii, M.; O'Hara, K.; Watanabe, S.; Karahashi, M.;
Kobayashi, M.; Hirano, H.: Mental retardation with hyperfolic acidemia
not associated with formiminoglutamic aciduria: cyclohydrolase deficiency
syndrome. Tohoku J. Exp. Med. 88: 341-352, 1966.

3. Barton, J. W.; Hart, I. M.; Patterson, D.: Mapping of a locus
correcting lack of phosphoribosylaminoimidazole carboxylase activity
in Chinese hamster ovary cell Ade-D mutants to human chromosome 4. Genomics 9:
314-321, 1991.

4. Brody, L. C.; Conley, M.; Cox, C.; Kirke, P. N.; McKeever, M. P.;
Mills, J. L.; Molloy, A. M.; O'Leary, V. B.; Parle-McDermott, A.;
Scott, J. M.; Swanson, D. A.: A polymorphism, R653Q, in the trifunctional
enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate
cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic
risk factor for neural tube defects: report of the birth defects research
group. Am. J. Hum. Genet. 71: 1207-1215, 2002.

5. De Marco, P.; Merello, E.; Calevo, M. G.; Mascelli, S.; Raso, A.;
Cama, A.; Capra, V.: Evaluation of a methylenetetrahydrofolate-dehydrogenase
1958G/A polymorphism for neural tube defect risk. J. Hum. Genet. 51:
98-103, 2006.

6. Henikoff, S.; Keene, M.; Sloan, J. S.; Bleskan, J.; Hards, R. G.;
Patterson, D.: Multiple purine pathway enzyme activities are encoded
at a single genetic locus in Drosophila. Proc. Nat. Acad. Sci. 83:
720-724, 1986.

7. Hol, F. A.; van der Put, N. M. J.; Geurds, M. P. A.; Heil, S. G.;
Trijbels, F. J. M.; Hamel, B. C. J.; Mariman, E. C. M.; Blom, H. J.
: Molecular genetic analysis of the gene encoding the trifunctional
enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase,
formyltetrahydrofolate synthetase) in patients with neural tube defects. Clin.
Genet. 53: 119-125, 1998.

8. Hum, D. W.; Bell, A. W.; Rozen, R.; MacKenzie, R. E.: Primary
structure of a human trifunctional enzyme: isolation of a cDNA encoding
methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate
synthetase. J. Biol. Chem. 263: 15946-15950, 1988.

9. Italiano, C.; John, S. W. M.; Hum, D. W.; MacKenzie, R. E.; Rozen,
R.: A pseudogene on the X chromosome for the human trifunctional
enzyme MTHFD (methylenetetrahydrofolate dehydrogenase--methenyltetrahydrofolate
cyclohydrolase--formyltetrahydrofolate synthetase). Genomics 10:
1073-1074, 1991.

10. Jones, C.; Patterson, D.; Kao, F.-T.: Assignment of the gene
coding for phosphoribosylglycineamide formyltransferase to human chromosome
14. Somat. Cell Genet. 7: 399-409, 1981.

11. Kao, F.-T.: Chromosomal assignment of the gene for phosphoribosyl
formylglycinamidine synthetase (PFGS) to human chromosome 14. (Abstract) J.
Cell Biol. 87: 291A only, 1980.

12. Kao, F.-T.; Puck, T. T.: Genetics of somatic mammalian cells:
demonstration of a human esterase activator gene linked to the adeb
gene. Proc. Nat. Acad. Sci. 69: 3273-3277, 1972.

13. Kao, F. T.; Zhang, X.; Law, M. L.; Jones, C.: Regional mapping
of GLYB (gly-B) to 8q21.1-qter and PGFT (phosphoribosylglycinamide
formyltransferase) to 14q22-qter. (Abstract) Cytogenet. Cell Genet. 37:
504-505, 1984.

14. Parle-McDermott, A.; Kirke, P. N.; Mills, J. L.; Molloy, A. M.;
Cox, C.; O'Leary, V. B.; Pangilinan, F.; Conley, M.; Cleary, L.; Brody,
L. C.; Scott, J. M.: Confirmation of the R653Q polymorphism of the
trifunctional C1-synthase enzyme as a maternal risk for neural tube
defects in the Irish population. Europ. J. Hum. Genet. 14: 768-772,
2006.

15. Parle-McDermott, A.; Mills, J. L.; Kirke, P. N.; Cox, C.; Signore,
C. C.; Kirke, S.; Molloy, A. M.; O'Leary, V. B.; Pangilinan, F. J.;
O'Herlihy, C.; Brody, L. C.; Scott, J. M.: MTHFD1 R653Q polymorphism
is a maternal genetic risk factor for severe abruptio placentae. Am.
J. Med. Genet. 132A: 365-368, 2005.

16. Patterson, D.: Personal Communication. Denver, Colo. 6/1/1986.

17. Rozen, R.; Barton, D.; Du, J.; Hum, D. W.; MacKenzie, R. E.; Francke,
U.: Chromosomal localization of the gene for the human trifunctional
enzyme, methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate
cyclohydrolase-formyltetrahydrofolate synthetase. Am. J. Hum. Genet. 44:
781-786, 1989.

18. Schild, D.; Brake, A. J.; Kiefer, M. C.; Young, D.; Barr, P. J.
: Cloning of three human multifunctional de novo purine biosynthetic
genes by functional complementation of yeast mutations. Proc. Nat.
Acad. Sci. 87: 2916-2920, 1990.

19. Van der Linden, I. J. M.; Heil, S. G.; Kouwenberg, I. C.; den
Heijer, M.; Blom, H. J.: The methylenetetrahydrofolate dehydrogenase
(MTHFD1) 1958G-A variant is not associated with spina bifida risk
in the Dutch population. (Letter) Clin. Genet. 72: 599-600, 2007.

20. Zdoukopoulos, N.; Zintzaras, E.: Genetic risk factors for placental
abruption: a HuGE review and meta-analysis. Epidemiology 19: 309-323,
2008.

*FIELD* CN
Cassandra L. Kniffin - updated: 1/14/2008
Marla J. F. O'Neill - updated: 8/29/2006
Cassandra L. Kniffin - reorganized: 7/31/2006
Marla J. F. O'Neill - updated: 4/6/2006
Marla J. F. O'Neill - updated: 3/1/2005
Victor A. McKusick - updated: 12/23/2002
Ada Hamosh - updated: 10/15/1998

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
carol: 04/30/2012
carol: 4/30/2012
carol: 1/21/2008
ckniffin: 1/14/2008
wwang: 8/30/2006
terry: 8/29/2006
ckniffin: 8/1/2006
carol: 7/31/2006
ckniffin: 7/26/2006
alopez: 6/9/2006
wwang: 4/7/2006
terry: 4/6/2006
wwang: 3/7/2005
terry: 3/1/2005
mgross: 3/17/2004
ckniffin: 5/28/2003
tkritzer: 3/4/2003
cwells: 1/6/2003
terry: 12/23/2002
psherman: 5/1/2000
alopez: 7/28/1999
dkim: 12/10/1998
carol: 10/18/1998
carol: 10/15/1998
carol: 9/2/1998
alopez: 6/2/1997
carol: 9/29/1994
terry: 7/15/1994
warfield: 4/12/1994
supermim: 3/16/1992
carol: 8/30/1991
carol: 8/9/1991

MIM 601634
*RECORD*
*FIELD* NO
601634
*FIELD* TI
#601634 NEURAL TUBE DEFECTS, FOLATE-SENSITIVE
;;NTD, FOLATE-SENSITIVE
SPINA BIFIDA, FOLATE-SENSITIVE, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because folate-sensitive
neural tube defects (NTD) have been associated with variations in a
number of genes involved in folate and homocysteine metabolism,
including 5,10-methylenetetrahydrofolate reductase (MTHFR; 607093),
methionine synthase (MTR; 156570), methionine synthase reductase (MTRR;
602568), and methylenetetrahydrofolate dehydrogenase-1 (MTHFD1; 172460).

See also (182940) for a discussion of neural tube defects that may not
be associated with folate metabolism. See also 601775 for a description
of variation of folate levels in erythrocytes.

DESCRIPTION

Neural tube defects have a birth incidence of approximately 1 in 1,000
in American Caucasians and are the second most common type of birth
defect after congenital heart defects. The most common NTDs are open
spina bifida (myelomeningocele) and anencephaly (206500) (Detrait et
al., 2005).

Women with elevated plasma homocysteine, low folate, or low vitamin B12
(cobalamin) are at increased risk of having a child with a neural tube
defect (O'Leary et al., 2005). Motulsky (1996) cited evidence from the
Centers for Disease Control ( Anonymous, 1992) that folic acid given
before and during the first 4 weeks of pregnancy can prevent 50% or more
of neural tube defects.

Botto et al. (1999) and Detrait et al. (2005) provided reviews of neural
tube defects. De Marco et al. (2006) provided a detailed review of
neurulation and the possible etiologies of neural tube defects.

PATHOGENESIS

Mills et al. (1996) reviewed the possible biochemical mechanisms by
which folic acid taken periconceptionally can prevent many neural tube
defects. They cited evidence that NTDs do not result primarily from a
nutritional deficiency of folic acid but rather from a metabolic defect
or defects that can be corrected by a sufficiently large dose of folic
acid. Their studies indicated that homocysteine metabolism is likely to
be the critical pathway affected by folic acid. Mills et al. (1996)
demonstrated significantly higher homocysteine levels in women carrying
NTD-affected fetuses, suggesting that one of the enzymes involved in
homocysteine metabolism is abnormal in NTD-affected pregnancies.

MOLECULAR GENETICS

Van der Put et al. (1995) found an increased frequency of the 677C-T
thermolabile MTHFR polymorphism (607093.0003) among 55 Dutch patients
with spina bifida and their parents compared to controls. Sixteen
percent of mothers, 10% of fathers, and 13% of patients were homozygous
for the variant compared to 5% of controls. Van der Put et al. (1995)
concluded that the 677C-T variant is a genetic risk factor for spina
bifida. Ou et al. (1996) studied fibroblast cultures from 41
NTD-affected fetuses and compared their genotypes with 109 blood
specimens from the general population. They demonstrated that 677C-T
homozygosity was associated with a 7.2-fold increased risk for NTD (p =
0.001). Ou et al. (1996) concluded that the 677C-T polymorphism of MTHFR
may provide a partial biologic explanation for the prevention of neural
tube defects by folic acid.

Christensen et al. (1999) assessed genotypes and folate status in 56
patients with spina bifida, 62 mothers of patients, 97 children without
NTDs (controls), and 90 mothers of controls to determine the impact of
these factors on NTD risk. In 20% of patients and 18% of mothers of
patients, they found homozygosity for the MTHFR 677C-T polymorphism,
compared to 11% of controls and 11% of control mothers, indicating that
the mutant genotype conferred an increased risk for NTDs. The risk was
further increased if both mother and child had this genotype. RBC folate
was lower in patients and in mothers of patients compared to their
respective controls. The combination of homozygous mutant MTHFR genotype
and RBC folate in the lowest quartile conferred an odds ratio for being
an NTD case of 13.43 and an odds ratio for having a child with NTD of
3.28. Christensen et al. (1999) proposed that the genetic-nutrient
interaction, i.e., MTHFR polymorphism and low folate status, is
associated with a greater risk for NTDs than either variable alone.

Among 56 patients with spina bifida and 58 mothers of children with
spina bifida, Wilson et al. (1999) found that patients and mothers of
patients were almost twice as likely to be homozygous for a 66A-G
polymorphism in the MTRR gene (602568.0003) compared to controls. When
combined with low levels of serum B12, the risk for mothers increased
nearly 5 times (odds ratio of 4.8); the OR for children with this
combination was 2.5. In the presence of combined MTHFR 677C-T and MTRR
66A-G homozygous mutant genotypes, children and mothers had a 4- and
3-fold increase in risk, respectively.

Doolin et al. (2002) analyzed data on the MTR 2756A-G polymorphism
(156570.0008) and the MTRR 66A-G polymorphism and concluded that both
variants influence the risk of spina bifida via the maternal rather than
the embryonic genotype. For both variants, the risk of having a child
with spina bifida appeared to increase with the number of high-risk
alleles in the maternal genotype.

Relton et al. (2004) conducted a case-control association study in
families affected by NTD to determine the contribution of polymorphic
variation in genes involved in the folate-dependent homocysteine
pathway. They investigated 7 polymorphisms in 6 genes: 2 in MTHFR and 1
each in MTRR, SHMT1 (182144), CBS (613381), GCP2 (600934), and RFC1
(600424). Both independent genetic effects and gene-gene interactions
were observed in relation to NTD risk. Maternal-fetal interaction was
also detected when offspring carried the MTHFR 677C-T variant and
mothers carried the MTRR 66A-G variant.

Hol et al. (1998) identified a heterozygous mutation in the MTHFD1 gene
(172460.0001) in 2 brothers with spina bifida, 1 with spina bifida
aperta and 1 with spina bifida occulta. The unaffected maternal
grandmother, mother, and a third brother also carried the mutation.

Brody et al. (2002) and De Marco et al. (2006) both observed an
association between an R653Q polymorphism in the MTHFD1 gene
(172460.0002) and neural tube defects in an Irish and Italian
population, respectively. Parle-McDermott et al. (2006) analyzed the
MTHFD1 gene in an independent sample of 245 Irish mothers with a history
of NDT-affected pregnancy and 770 controls and found a significant
excess of QQ homozygote mothers of NTD cases compared to controls (OR,
1.49; p = 0.019). Parle-McDermott et al. (2006) concluded that the R653Q
polymorphism has a significant role in influencing a mother's risk of
having an NTD-affected pregnancy in the Irish population.

O'Leary et al. (2005) found no association between the MTRR 66A-G
polymorphism and neural tube defects in an Irish population comprising
470 patients and 447 mothers of patients. A dominant paternal effect was
observed (OR, 1.46).

Mildly elevated maternal plasma homocysteine levels have been observed
in some NTD pregnancies. In the NTD population in Ireland, Ramsbottom et
al. (1997) examined the frequency of relatively common mutations in the
gene encoding cystathionine beta-synthase (236200), one of the main
enzymes that controls homocysteine levels. Neither the severely
dysfunctional G307S CBS allele (236200.0001) nor the allele with the
68-bp insertion in exon 8 in association with the I278T CBS mutation
(236200.0004) was observed in increased frequency in the cases relative
to controls. Ramsbottom et al. (1997) concluded that loss-of-function
CBS alleles do not account for NTD in Ireland.

ANIMAL MODEL

To investigate the mechanism whereby folate supplementation protects
against heart and neural tube defects, Rosenquist et al. (1996) tested
the effects of homocysteine on chick embryos and the effect of added
folate. The hypothesis was that homocysteine may be the teratogenic
agent, since serum homocysteine increases in folate depletion. Of
embryos treated with homocysteine or homocysteine thiolactone, 27%
showed neural tube defects. A high frequency of ventricular septal
defects and neural tube defects was observed. Also, a ventral closure
defect was found in a high percentage of day 9 embryos. The teratogenic
dose was shown to raise serum homocysteine to over 150 nmol/ml, compared
with a normal level of about 10 nmol/ml. F1late supplementation kept the
rise in serum homocysteine to approximately 45 nmol/ml and prevented the
teratogenic effect. Rosenquist et al. (1996) concluded that homocysteine
per se causes dysmorphogenesis of the heart and neural tube, as well as
of the ventral wall.

Carter et al. (1999) examined whether 'crooked tail' (Cd), a mouse
strain prone to exencephaly, could provide a genetic animal model for
folate-responsive neural tube defects. They localized the Cd locus to a
0.2-cM interval on mouse distal chromosome 6, identifying tightly linked
markers for genotyping prior to phenotypic expression. In a controlled
diet study, Cd was found to mimic closely the clinical response to folic
acid observed in human populations. Folic acid supplementation reduced
the recurrence risk of Cd exencephaly by as much as 55%. This rescue was
dose dependent and did not require subjects to be inherently folate
deficient. Like the female predominance of NTDs in humans, female Cd
embryos were most likely to display exencephaly and were more responsive
than males to the folic acid rescue. Importantly, folic acid
supplementation shifted the severity of Cd phenotypic expression from
early embryonic lethality to longer survival, and reduced the incidence
of NTDs. Carter et al. (2005) found that the Cd mouse is caused by a
heterozygous G494D mutation in a highly conserved region of the Lrp6
gene (603507). Functional expression studies showed that mutant Lrp6
protein resulted in Wnt (164820) hyperactivity. The findings provided a
functional connection between Wnt signaling and folate rescue of neural
tube defects in mouse, even though these proteins are not directly
involved in folate metabolism.

Juriloff and Harris (2000) reviewed the numerous mouse models of NTDs,
as well as the zonal pattern of neural tube closure and the effect of
maternal nutrients on neural tube closure.

*FIELD* SA
Frosst et al. (1995)
*FIELD* RF
1. Anonymous: Recommendations for the use of folic acid to reduce
the number of cases of spina bifida and other neural tube defects. MMWR
Morb. Mortal. Wkly. Rep. 41 (Rr-14): 1-7, 1992.

2. Botto, L. D.; Moore, C. A.; Khoury, M. J.; Erickson, J. D.: Neural-tube
defects. New Eng. J. Med. 341: 1509-1519, 1999.

3. Brody, L. C.; Conley, M.; Cox, C.; Kirke, P. N.; McKeever, M. P.;
Mills, J. L.; Molloy, A. M.; O'Leary, V. B.; Parle-McDermott, A.;
Scott, J. M.; Swanson, D. A.: A polymorphism, R653Q, in the trifunctional
enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate
cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic
risk factor for neural tube defects: report of the birth defects research
group. Am. J. Hum. Genet. 71: 1207-1215, 2002.

4. Carter, M.; Chen, X.; Slowinska, B.; Minnerath, S.; Glickstein,
S.; Shi, L.; Campagne, F.; Weinstein, H.; Ross, M. E.: Crooked tail
(Cd) model of human folate-responsive neural tube defects is mutated
in Wnt coreceptor lipoprotein receptor-related protein 6. Proc. Nat.
Acad. Sci. 102: 12843-12848, 2005.

5. Carter, M.; Ulrich, S.; Oofuji, Y.; Williams, D. A.; Ross, M. E.
: Crooked tail (Cd) models human folate-responsive neural tube defects. Hum.
Molec. Genet. 8: 2199-2204, 1999.

6. 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.: Genetic polymorphisms in methylenetetrahydrofolate
reductase and methionine synthase, folate levels in red blood cells,
and risk of neural tube defects. Am. J. Med. Genet. 84: 151-157,
1999.

7. De Marco, P.; Merello, E.; Calevo, M. G.; Mascelli, S.; Raso, A.;
Cama, A.; Capra, V.: Evaluation of a methylenetetrahydrofolate-dehydrogenase
1958G/A polymorphism for neural tube defect risk. J. Hum. Genet. 51:
98-103, 2006.

8. De Marco, P.; Merello, E.; Mascelli, S.; Capra, V.: Current perspectives
on the genetic causes of neural tube defects. Neurogenetics 7: 201-221,
2006.

9. Detrait, E. R.; George, T. M.; Etchevers, H. C.; Gilbert, J. R.;
Vekemans, M.; Speer, M. C.: Human neural tube defects: developmental
biology, epidemiology, and genetics. Neurotox. Teratol. 27: 515-524,
2005.

10. Doolin, M.-T.; Barbaux, S.; McDonnell, M.; Hoess, K.; Whitehead,
A. S.; Mitchell, L. E.: Maternal genetic effects, exerted by genes
involved in homocysteine remethylation, influence the risk of spina
bifida. Am. J. Hum. Genet. 71: 1222-1226, 2002.

11. 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.: A candidate genetic risk
factor for vascular disease: a common mutation in methylenetetrahydrofolate
reductase. Nature Genet. 10: 111-113, 1995.

12. Hol, F. A.; van der Put, N. M. J.; Geurds, M. P. A.; Heil, S.
G.; Trijbels, F. J. M.; Hamel, B. C. J.; Mariman, E. C. M.; Blom,
H. J.: Molecular genetic analysis of the gene encoding the trifunctional
enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase,
formyltetrahydrofolate synthetase) in patients with neural tube defects. Clin.
Genet. 53: 119-125, 1998.

13. Juriloff, D. M.; Harris, M. J.: Mouse models for neural tube
closure defects. Hum. Molec. Genet. 9: 993-1000, 2000.

14. Mills, J. L.; Scott, J. M.; Kirke, P. N.; McPartlin, J. M.; Conley,
M. R.; Weir, D. G.; Molloy, A. M.; Lee, Y. J.: Homocysteine and neural
tube defects. J. Nutr. 126: 756S-760S, 1996.

15. Motulsky, A. G.: Nutritional ecogenetics: homocysteine-related
arteriosclerotic vascular disease, neural tube defects, and folic
acid. (Editorial) Am. J. Hum. Genet. 58: 17-20, 1996. Note: Erratum:
Am. J. Hum. Genet. 58: 648 only, 1996.

16. O'Leary, V. B.; Mills, J. L.; Pangilinan, F.; Kirke, P. N.; Cox,
C.; Conley, M.; Weiler, A.; Peng, K.; Shane, B.; Scott, J. M.; Parle-McDermott,
A.; Molloy, A. M.; Brody, L. C.; Members of the Birth Defects Research
Group: Analysis of methionine synthase reductase polymorphisms for
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*FIELD* CS

Metabolic:
Maternal abnormal homocysteine metabolism.

Misc:
Increased (7-fold) risk for NTD;
Folate-sensitive

Lab:
Thermolabile form of MTHFR

Inheritance:
? Autosomal recessive

*FIELD* CD
John F. Jackson: 09/23/1998

*FIELD* CN
Cassandra L. Kniffin - updated: 4/27/2007
Cassandra L. Kniffin - updated: 12/7/2006
Marla J. F. O'Neill - updated: 8/29/2006
Cassandra L. Kniffin - reorganized: 7/31/2006
Cassandra L. Kniffin - updated: 7/26/2006
Victor A. McKusick - updated: 4/29/2004
Victor A. McKusick - updated: 7/2/2002
Victor A. McKusick - updated: 2/11/2000
Victor A. McKusick - updated: 11/19/1999
Victor A. McKusick - updated: 5/10/1999
Victor A. McKusick - updated: 4/21/1997

*FIELD* CD
Moyra Smith: 1/17/1997

*FIELD* ED
terry: 09/07/2012
carol: 5/4/2010
ckniffin: 4/26/2010
wwang: 5/21/2007
ckniffin: 4/27/2007
wwang: 12/7/2006
ckniffin: 12/7/2006
wwang: 8/30/2006
terry: 8/29/2006
carol: 7/31/2006
ckniffin: 7/26/2006
tkritzer: 4/30/2004
terry: 4/29/2004
tkritzer: 2/28/2003
cwells: 7/30/2002
ckniffin: 7/9/2002
terry: 7/2/2002
carol: 2/11/2000
carol: 11/23/1999
terry: 11/19/1999
carol: 5/18/1999
mgross: 5/12/1999
terry: 5/10/1999
mark: 4/21/1997
terry: 4/21/1997
mark: 1/21/1997
mark: 1/17/1997
terry: 1/17/1997
mark: 1/17/1997