Full text data of FTO
FTO
(KIAA1752)
[Confidence: low (only semi-automatic identification from reviews)]
Alpha-ketoglutarate-dependent dioxygenase FTO; 1.14.11.- (Fat mass and obesity-associated protein)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Alpha-ketoglutarate-dependent dioxygenase FTO; 1.14.11.- (Fat mass and obesity-associated protein)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q9C0B1
ID FTO_HUMAN Reviewed; 505 AA.
AC Q9C0B1; A2RUH1; B2RNS0; Q0P676; Q7Z785;
DT 01-MAY-2007, integrated into UniProtKB/Swiss-Prot.
read moreDT 29-MAY-2007, sequence version 3.
DT 22-JAN-2014, entry version 82.
DE RecName: Full=Alpha-ketoglutarate-dependent dioxygenase FTO;
DE EC=1.14.11.-;
DE AltName: Full=Fat mass and obesity-associated protein;
GN Name=FTO; Synonyms=KIAA1752;
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 [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=11214970; DOI=10.1093/dnares/7.6.347;
RA Nagase T., Kikuno R., Hattori A., Kondo Y., Okumura K., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XIX.
RT The complete sequences of 100 new cDNA clones from brain which code
RT for large proteins in vitro.";
RL DNA Res. 7:347-355(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC TISSUE=Brain;
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X.,
RA Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A.,
RA Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J.,
RA Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L.,
RA Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A.,
RA Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D.,
RA Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J.,
RA Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I.,
RA Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W.,
RA Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A.,
RA Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S.,
RA Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L.,
RA Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A.,
RA Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L.,
RA Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N.,
RA Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M.,
RA Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L.,
RA Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D.,
RA Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P.,
RA Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M.,
RA Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 3 AND 4).
RC TISSUE=Cervix, Eye, and Lung;
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 [4]
RP INVOLVEMENT IN PREDISPOSITION OF OBESITY, AND TISSUE SPECIFICITY.
RX PubMed=17496892; DOI=10.1038/ng2048;
RA Dina C., Meyre D., Gallina S., Durand E., Korner A., Jacobson P.,
RA Carlsson L.M.S., Kiess W., Vatin V., Lecoeur C., Delplanque J.,
RA Vaillant E., Pattou F., Ruiz J., Weill J., Levy-Marchal C., Horber F.,
RA Potoczna N., Hercberg S., Le Stunff C., Bougneres P., Kovacs P.,
RA Marre M., Balkau B., Cauchi S., Chevre J.-C., Froguel P.;
RT "Variation in FTO contributes to childhood obesity and severe adult
RT obesity.";
RL Nat. Genet. 39:724-726(2007).
RN [5]
RP INVOLVEMENT IN PREDISPOSITION OF OBESITY, AND TISSUE SPECIFICITY.
RX PubMed=17434869; DOI=10.1126/science.1141634;
RA Frayling T.M., Timpson N.J., Weedon M.N., Zeggini E., Freathy R.M.,
RA Lindgren C.M., Perry J.R., Elliott K.S., Lango H., Rayner N.W.,
RA Shields B., Harries L.W., Barrett J.C., Ellard S., Groves C.J.,
RA Knight B., Patch A.M., Ness A.R., Ebrahim S., Lawlor D.A., Ring S.M.,
RA Ben-Shlomo Y., Jarvelin M.-R., Sovio U., Bennett A.J., Melzer D.,
RA Ferrucci L., Loos R.J., Barroso I., Wareham N.J., Karpe F., Owen K.R.,
RA Cardon L.R., Walker M., Hitman G.A., Palmer C.N., Doney A.S.,
RA Morris A.D., Davey-Smith G., Hattersley A.T., McCarthy M.I.;
RT "A common variant in the FTO gene is associated with body mass index
RT and predisposes to childhood and adult obesity.";
RL Science 316:889-894(2007).
RN [6]
RP FUNCTION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=18775698; DOI=10.1016/j.febslet.2008.08.019;
RA Jia G., Yang C.G., Yang S., Jian X., Yi C., Zhou Z., He C.;
RT "Oxidative demethylation of 3-methylthymine and 3-methyluracil in
RT single-stranded DNA and RNA by mouse and human FTO.";
RL FEBS Lett. 582:3313-3319(2008).
RN [7]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-216, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [8]
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 [9]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 32-505 IN COMPLEX WITH IRON
RP IONS; N-OXALYLGLYCINE AND 3-METHYLTHYMIDINE, CATALYTIC ACTIVITY,
RP FUNCTION, COFACTOR, ENZYME REGULATION, MUTAGENESIS OF ARG-96; TYR-108;
RP PHE-114; GLU-234 AND CYS-392, CIRCULAR DICHROISM, AND DOMAIN.
RX PubMed=20376003; DOI=10.1038/nature08921;
RA Han Z., Niu T., Chang J., Lei X., Zhao M., Wang Q., Cheng W., Wang J.,
RA Feng Y., Chai J.;
RT "Crystal structure of the FTO protein reveals basis for its substrate
RT specificity.";
RL Nature 464:1205-1209(2010).
RN [10]
RP VARIANT GDFD GLN-316, AND CHARACTERIZATION OF VARIANT GDFD GLN-316.
RX PubMed=19559399; DOI=10.1016/j.ajhg.2009.06.002;
RA Boissel S., Reish O., Proulx K., Kawagoe-Takaki H., Sedgwick B.,
RA Yeo G.S., Meyre D., Golzio C., Molinari F., Kadhom N., Etchevers H.C.,
RA Saudek V., Farooqi I.S., Froguel P., Lindahl T., O'Rahilly S.,
RA Munnich A., Colleaux L.;
RT "Loss-of-function mutation in the dioxygenase-encoding FTO gene causes
RT severe growth retardation and multiple malformations.";
RL Am. J. Hum. Genet. 85:106-111(2009).
CC -!- FUNCTION: Dioxygenase that repairs alkylated DNA and RNA by
CC oxidative demethylation. Has highest activity towards single-
CC stranded RNA containing 3-methyluracil, followed by single-
CC stranded DNA containing 3-methylthymine. Has low demethylase
CC activity towards single-stranded DNA containing 1-methyladenine or
CC 3-methylcytosine. Has no activity towards 1-methylguanine. Has no
CC detectable activity towards double-stranded DNA. Requires
CC molecular oxygen, alpha-ketoglutarate and iron. Contributes to the
CC regulation of the global metabolic rate, energy expenditure and
CC energy homeostasis. Contributes to the regulation of body size and
CC body fat accumulation.
CC -!- COFACTOR: Binds 1 Fe(2+) ion per subunit.
CC -!- ENZYME REGULATION: Activated by ascorbate. Inhibited by N-
CC oxalylglycine, fumarate and succinate (By similarity).
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC pH dependence:
CC Optimum pH is 5.5-6;
CC -!- SUBUNIT: Monomer. May also exist as homodimer (By similarity).
CC -!- SUBCELLULAR LOCATION: Nucleus (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q9C0B1-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9C0B1-2; Sequence=VSP_025004, VSP_025005;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=Q9C0B1-3; Sequence=VSP_025002, VSP_025006;
CC Note=No experimental confirmation available;
CC Name=4;
CC IsoId=Q9C0B1-4; Sequence=VSP_025003;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed, with relatively high
CC expression in adrenal glands and brain; especially in hypothalamus
CC and pituitary.
CC -!- DOMAIN: The 3D-structure of the Fe2OG dioxygenase domain is
CC similar to that of the Fe2OG dioxygenase domain found in the
CC bacterial DNA repair dioxygenase alkB and its mammalian orthologs,
CC but sequence similarity is very low. As a consequence, the domain
CC is not detected by protein signature databases.
CC -!- POLYMORPHISM: At least one intronic variation within the gene
CC predisposes to childhood and adult obesity.
CC -!- DISEASE: Growth retardation developmental delay coarse facies
CC early death (GDFD) [MIM:612938]: A severe polymalformation
CC syndrome characterized by postnatal growth retardation,
CC microcephaly, severe psychomotor delay, functional brain deficits
CC and characteristic facial dysmorphism. In some patients,
CC structural brain malformations, cardiac defects, genital
CC anomalies, and cleft palate are observed. Early death occurs by
CC the age of 3 years. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the fto family.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB21843.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
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DR EMBL; AB051539; BAB21843.1; ALT_INIT; mRNA.
DR EMBL; AC007347; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC007496; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC007909; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC003583; AAH03583.1; -; mRNA.
DR EMBL; BC030798; AAH30798.1; -; mRNA.
DR EMBL; BC132892; AAI32893.1; -; mRNA.
DR EMBL; BC137091; AAI37092.1; -; mRNA.
DR RefSeq; NP_001073901.1; NM_001080432.2.
DR UniGene; Hs.528833; -.
DR PDB; 3LFM; X-ray; 2.50 A; A=32-505.
DR PDB; 4IDZ; X-ray; 2.46 A; A=32-505.
DR PDB; 4IE0; X-ray; 2.53 A; A=32-505.
DR PDB; 4IE4; X-ray; 2.50 A; A=32-505.
DR PDB; 4IE5; X-ray; 1.95 A; A=32-505.
DR PDB; 4IE6; X-ray; 2.50 A; A=32-505.
DR PDB; 4IE7; X-ray; 2.60 A; A=32-505.
DR PDBsum; 3LFM; -.
DR PDBsum; 4IDZ; -.
DR PDBsum; 4IE0; -.
DR PDBsum; 4IE4; -.
DR PDBsum; 4IE5; -.
DR PDBsum; 4IE6; -.
DR PDBsum; 4IE7; -.
DR ProteinModelPortal; Q9C0B1; -.
DR SMR; Q9C0B1; 30-503.
DR IntAct; Q9C0B1; 2.
DR STRING; 9606.ENSP00000418823; -.
DR ChEMBL; CHEMBL2331065; -.
DR PhosphoSite; Q9C0B1; -.
DR DMDM; 148841515; -.
DR PaxDb; Q9C0B1; -.
DR PRIDE; Q9C0B1; -.
DR DNASU; 79068; -.
DR Ensembl; ENST00000431610; ENSP00000415636; ENSG00000140718.
DR Ensembl; ENST00000460382; ENSP00000417422; ENSG00000140718.
DR Ensembl; ENST00000463855; ENSP00000417843; ENSG00000140718.
DR Ensembl; ENST00000471389; ENSP00000418823; ENSG00000140718.
DR GeneID; 79068; -.
DR KEGG; hsa:79068; -.
DR UCSC; uc002ehr.3; human.
DR CTD; 79068; -.
DR GeneCards; GC16P053737; -.
DR H-InvDB; HIX0013037; -.
DR H-InvDB; HIX0134382; -.
DR H-InvDB; HIX0204005; -.
DR HGNC; HGNC:24678; FTO.
DR HPA; CAB017123; -.
DR MIM; 610966; gene.
DR MIM; 612938; phenotype.
DR neXtProt; NX_Q9C0B1; -.
DR Orphanet; 210144; Lethal polymalformative syndrome, Boissel type.
DR PharmGKB; PA152208656; -.
DR eggNOG; NOG45792; -.
DR HOGENOM; HOG000273870; -.
DR HOVERGEN; HBG101847; -.
DR InParanoid; Q9C0B1; -.
DR OMA; AVYNYSC; -.
DR OrthoDB; EOG7CK36T; -.
DR PhylomeDB; Q9C0B1; -.
DR ChiTaRS; FTO; human.
DR GeneWiki; FTO_gene; -.
DR GenomeRNAi; 79068; -.
DR NextBio; 67845; -.
DR PRO; PR:Q9C0B1; -.
DR ArrayExpress; Q9C0B1; -.
DR Bgee; Q9C0B1; -.
DR CleanEx; HS_FTO; -.
DR Genevestigator; Q9C0B1; -.
DR GO; GO:0005634; C:nucleus; ISS:BHF-UCL.
DR GO; GO:0043734; F:DNA-N1-methyladenine dioxygenase activity; IDA:UniProtKB.
DR GO; GO:0008198; F:ferrous iron binding; IDA:UniProtKB.
DR GO; GO:0035516; F:oxidative DNA demethylase activity; IDA:UniProtKB.
DR GO; GO:0035515; F:oxidative RNA demethylase activity; IDA:BHF-UCL.
DR GO; GO:0060612; P:adipose tissue development; IEA:Ensembl.
DR GO; GO:0006307; P:DNA dealkylation involved in DNA repair; IDA:UniProtKB.
DR GO; GO:0035552; P:oxidative single-stranded DNA demethylation; IDA:UniProtKB.
DR GO; GO:0035553; P:oxidative single-stranded RNA demethylation; IDA:BHF-UCL.
DR GO; GO:0010883; P:regulation of lipid storage; IEA:Ensembl.
DR GO; GO:0040014; P:regulation of multicellular organism growth; IEA:Ensembl.
DR GO; GO:0044065; P:regulation of respiratory system process; IEA:Ensembl.
DR GO; GO:0070350; P:regulation of white fat cell proliferation; IEA:Ensembl.
DR GO; GO:0042245; P:RNA repair; IDA:BHF-UCL.
DR GO; GO:0001659; P:temperature homeostasis; IEA:Ensembl.
DR InterPro; IPR024366; FTO_C.
DR InterPro; IPR024367; FTO_cat_dom.
DR Pfam; PF12934; FTO_CTD; 1.
DR Pfam; PF12933; FTO_NTD; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Dioxygenase; Disease mutation; DNA damage; DNA repair; Iron;
KW Metal-binding; Nucleus; Obesity; Oxidoreductase; Polymorphism;
KW Reference proteome; RNA repair.
FT CHAIN 1 505 Alpha-ketoglutarate-dependent dioxygenase
FT FTO.
FT /FTId=PRO_0000286163.
FT REGION 32 327 Fe2OG dioxygenase domain.
FT REGION 213 224 Loop L1; predicted to block binding of
FT double-stranded DNA or RNA.
FT REGION 231 234 Substrate binding.
FT REGION 316 318 Alpha-ketoglutarate binding.
FT METAL 231 231 Iron; catalytic.
FT METAL 233 233 Iron; catalytic.
FT METAL 307 307 Iron; catalytic.
FT BINDING 96 96 Substrate.
FT BINDING 108 108 Substrate.
FT BINDING 205 205 Alpha-ketoglutarate.
FT BINDING 295 295 Alpha-ketoglutarate.
FT BINDING 320 320 Alpha-ketoglutarate.
FT BINDING 322 322 Alpha-ketoglutarate.
FT MOD_RES 216 216 N6-acetyllysine.
FT VAR_SEQ 1 445 Missing (in isoform 3).
FT /FTId=VSP_025002.
FT VAR_SEQ 1 399 Missing (in isoform 4).
FT /FTId=VSP_025003.
FT VAR_SEQ 1 378 Missing (in isoform 2).
FT /FTId=VSP_025004.
FT VAR_SEQ 379 413 LRQFWFQGNRYRKCTDWWCQPMAQLEALWKKMEGV -> ME
FT WRKVSECNSVEPCREVKKWPYRCIHHGKNFSRM (in
FT isoform 2).
FT /FTId=VSP_025005.
FT VAR_SEQ 446 455 QNLRREWHAR -> MACQGREECW (in isoform 3).
FT /FTId=VSP_025006.
FT VARIANT 316 316 R -> Q (in GDFD; has no residual normal
FT activity).
FT /FTId=VAR_063252.
FT VARIANT 405 405 A -> V (in dbSNP:rs16952624).
FT /FTId=VAR_032078.
FT MUTAGEN 96 96 R->M,W: Almost abolishes enzyme activity.
FT MUTAGEN 108 108 Y->A: Abolishes enzyme activity.
FT MUTAGEN 114 114 F->D: Perturbs interaction between N-
FT terminal and C-terminal domains and
FT strongly reduces enzyme activity.
FT MUTAGEN 234 234 E->P: Abolishes enzyme activity.
FT MUTAGEN 392 392 C->D: Perturbs interaction between N-
FT terminal and C-terminal domains and
FT strongly reduces enzyme activity.
FT CONFLICT 316 316 R -> W (in Ref. 1; BAB21843 and 3;
FT AAH03583/AAH30798/AAI32893).
FT HELIX 38 45
FT STRAND 49 52
FT HELIX 54 56
FT HELIX 59 74
FT STRAND 79 85
FT STRAND 88 101
FT STRAND 104 108
FT STRAND 111 114
FT HELIX 130 162
FT HELIX 190 196
FT STRAND 201 207
FT TURN 209 211
FT STRAND 212 214
FT STRAND 219 221
FT STRAND 225 231
FT STRAND 242 248
FT STRAND 271 276
FT STRAND 280 282
FT STRAND 284 288
FT STRAND 293 297
FT HELIX 301 304
FT STRAND 305 310
FT STRAND 316 322
FT HELIX 331 342
FT HELIX 361 377
FT HELIX 379 384
FT TURN 385 387
FT HELIX 389 391
FT HELIX 397 422
FT STRAND 423 426
FT HELIX 428 457
FT HELIX 459 463
FT HELIX 466 468
FT STRAND 483 485
FT HELIX 490 500
SQ SEQUENCE 505 AA; 58282 MW; 3498A92C6E6D81B1 CRC64;
MKRTPTAEER EREAKKLRLL EELEDTWLPY LTPKDDEFYQ QWQLKYPKLI LREASSVSEE
LHKEVQEAFL TLHKHGCLFR DLVRIQGKDL LTPVSRILIG NPGCTYKYLN TRLFTVPWPV
KGSNIKHTEA EIAAACETFL KLNDYLQIET IQALEELAAK EKANEDAVPL CMSADFPRVG
MGSSYNGQDE VDIKSRAAYN VTLLNFMDPQ KMPYLKEEPY FGMGKMAVSW HHDENLVDRS
AVAVYSYSCE GPEEESEDDS HLEGRDPDIW HVGFKISWDI ETPGLAIPLH QGDCYFMLDD
LNATHQHCVL AGSQPRFSST HRVAECSTGT LDYILQRCQL ALQNVCDDVD NDDVSLKSFE
PAVLKQGEEI HNEVEFEWLR QFWFQGNRYR KCTDWWCQPM AQLEALWKKM EGVTNAVLHE
VKREGLPVEQ RNEILTAILA SLTARQNLRR EWHARCQSRI ARTLPADQKP ECRPYWEKDD
ASMPLPFDLT DIVSELRGQL LEAKP
//
ID FTO_HUMAN Reviewed; 505 AA.
AC Q9C0B1; A2RUH1; B2RNS0; Q0P676; Q7Z785;
DT 01-MAY-2007, integrated into UniProtKB/Swiss-Prot.
read moreDT 29-MAY-2007, sequence version 3.
DT 22-JAN-2014, entry version 82.
DE RecName: Full=Alpha-ketoglutarate-dependent dioxygenase FTO;
DE EC=1.14.11.-;
DE AltName: Full=Fat mass and obesity-associated protein;
GN Name=FTO; Synonyms=KIAA1752;
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 [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=11214970; DOI=10.1093/dnares/7.6.347;
RA Nagase T., Kikuno R., Hattori A., Kondo Y., Okumura K., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XIX.
RT The complete sequences of 100 new cDNA clones from brain which code
RT for large proteins in vitro.";
RL DNA Res. 7:347-355(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC TISSUE=Brain;
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X.,
RA Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A.,
RA Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J.,
RA Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L.,
RA Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A.,
RA Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D.,
RA Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J.,
RA Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I.,
RA Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W.,
RA Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A.,
RA Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S.,
RA Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L.,
RA Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A.,
RA Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L.,
RA Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N.,
RA Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M.,
RA Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L.,
RA Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D.,
RA Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P.,
RA Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M.,
RA Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 3 AND 4).
RC TISSUE=Cervix, Eye, and Lung;
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 [4]
RP INVOLVEMENT IN PREDISPOSITION OF OBESITY, AND TISSUE SPECIFICITY.
RX PubMed=17496892; DOI=10.1038/ng2048;
RA Dina C., Meyre D., Gallina S., Durand E., Korner A., Jacobson P.,
RA Carlsson L.M.S., Kiess W., Vatin V., Lecoeur C., Delplanque J.,
RA Vaillant E., Pattou F., Ruiz J., Weill J., Levy-Marchal C., Horber F.,
RA Potoczna N., Hercberg S., Le Stunff C., Bougneres P., Kovacs P.,
RA Marre M., Balkau B., Cauchi S., Chevre J.-C., Froguel P.;
RT "Variation in FTO contributes to childhood obesity and severe adult
RT obesity.";
RL Nat. Genet. 39:724-726(2007).
RN [5]
RP INVOLVEMENT IN PREDISPOSITION OF OBESITY, AND TISSUE SPECIFICITY.
RX PubMed=17434869; DOI=10.1126/science.1141634;
RA Frayling T.M., Timpson N.J., Weedon M.N., Zeggini E., Freathy R.M.,
RA Lindgren C.M., Perry J.R., Elliott K.S., Lango H., Rayner N.W.,
RA Shields B., Harries L.W., Barrett J.C., Ellard S., Groves C.J.,
RA Knight B., Patch A.M., Ness A.R., Ebrahim S., Lawlor D.A., Ring S.M.,
RA Ben-Shlomo Y., Jarvelin M.-R., Sovio U., Bennett A.J., Melzer D.,
RA Ferrucci L., Loos R.J., Barroso I., Wareham N.J., Karpe F., Owen K.R.,
RA Cardon L.R., Walker M., Hitman G.A., Palmer C.N., Doney A.S.,
RA Morris A.D., Davey-Smith G., Hattersley A.T., McCarthy M.I.;
RT "A common variant in the FTO gene is associated with body mass index
RT and predisposes to childhood and adult obesity.";
RL Science 316:889-894(2007).
RN [6]
RP FUNCTION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=18775698; DOI=10.1016/j.febslet.2008.08.019;
RA Jia G., Yang C.G., Yang S., Jian X., Yi C., Zhou Z., He C.;
RT "Oxidative demethylation of 3-methylthymine and 3-methyluracil in
RT single-stranded DNA and RNA by mouse and human FTO.";
RL FEBS Lett. 582:3313-3319(2008).
RN [7]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-216, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [8]
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 [9]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 32-505 IN COMPLEX WITH IRON
RP IONS; N-OXALYLGLYCINE AND 3-METHYLTHYMIDINE, CATALYTIC ACTIVITY,
RP FUNCTION, COFACTOR, ENZYME REGULATION, MUTAGENESIS OF ARG-96; TYR-108;
RP PHE-114; GLU-234 AND CYS-392, CIRCULAR DICHROISM, AND DOMAIN.
RX PubMed=20376003; DOI=10.1038/nature08921;
RA Han Z., Niu T., Chang J., Lei X., Zhao M., Wang Q., Cheng W., Wang J.,
RA Feng Y., Chai J.;
RT "Crystal structure of the FTO protein reveals basis for its substrate
RT specificity.";
RL Nature 464:1205-1209(2010).
RN [10]
RP VARIANT GDFD GLN-316, AND CHARACTERIZATION OF VARIANT GDFD GLN-316.
RX PubMed=19559399; DOI=10.1016/j.ajhg.2009.06.002;
RA Boissel S., Reish O., Proulx K., Kawagoe-Takaki H., Sedgwick B.,
RA Yeo G.S., Meyre D., Golzio C., Molinari F., Kadhom N., Etchevers H.C.,
RA Saudek V., Farooqi I.S., Froguel P., Lindahl T., O'Rahilly S.,
RA Munnich A., Colleaux L.;
RT "Loss-of-function mutation in the dioxygenase-encoding FTO gene causes
RT severe growth retardation and multiple malformations.";
RL Am. J. Hum. Genet. 85:106-111(2009).
CC -!- FUNCTION: Dioxygenase that repairs alkylated DNA and RNA by
CC oxidative demethylation. Has highest activity towards single-
CC stranded RNA containing 3-methyluracil, followed by single-
CC stranded DNA containing 3-methylthymine. Has low demethylase
CC activity towards single-stranded DNA containing 1-methyladenine or
CC 3-methylcytosine. Has no activity towards 1-methylguanine. Has no
CC detectable activity towards double-stranded DNA. Requires
CC molecular oxygen, alpha-ketoglutarate and iron. Contributes to the
CC regulation of the global metabolic rate, energy expenditure and
CC energy homeostasis. Contributes to the regulation of body size and
CC body fat accumulation.
CC -!- COFACTOR: Binds 1 Fe(2+) ion per subunit.
CC -!- ENZYME REGULATION: Activated by ascorbate. Inhibited by N-
CC oxalylglycine, fumarate and succinate (By similarity).
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC pH dependence:
CC Optimum pH is 5.5-6;
CC -!- SUBUNIT: Monomer. May also exist as homodimer (By similarity).
CC -!- SUBCELLULAR LOCATION: Nucleus (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q9C0B1-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9C0B1-2; Sequence=VSP_025004, VSP_025005;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=Q9C0B1-3; Sequence=VSP_025002, VSP_025006;
CC Note=No experimental confirmation available;
CC Name=4;
CC IsoId=Q9C0B1-4; Sequence=VSP_025003;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed, with relatively high
CC expression in adrenal glands and brain; especially in hypothalamus
CC and pituitary.
CC -!- DOMAIN: The 3D-structure of the Fe2OG dioxygenase domain is
CC similar to that of the Fe2OG dioxygenase domain found in the
CC bacterial DNA repair dioxygenase alkB and its mammalian orthologs,
CC but sequence similarity is very low. As a consequence, the domain
CC is not detected by protein signature databases.
CC -!- POLYMORPHISM: At least one intronic variation within the gene
CC predisposes to childhood and adult obesity.
CC -!- DISEASE: Growth retardation developmental delay coarse facies
CC early death (GDFD) [MIM:612938]: A severe polymalformation
CC syndrome characterized by postnatal growth retardation,
CC microcephaly, severe psychomotor delay, functional brain deficits
CC and characteristic facial dysmorphism. In some patients,
CC structural brain malformations, cardiac defects, genital
CC anomalies, and cleft palate are observed. Early death occurs by
CC the age of 3 years. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the fto family.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB21843.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -----------------------------------------------------------------------
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DR EMBL; AB051539; BAB21843.1; ALT_INIT; mRNA.
DR EMBL; AC007347; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC007496; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC007909; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC003583; AAH03583.1; -; mRNA.
DR EMBL; BC030798; AAH30798.1; -; mRNA.
DR EMBL; BC132892; AAI32893.1; -; mRNA.
DR EMBL; BC137091; AAI37092.1; -; mRNA.
DR RefSeq; NP_001073901.1; NM_001080432.2.
DR UniGene; Hs.528833; -.
DR PDB; 3LFM; X-ray; 2.50 A; A=32-505.
DR PDB; 4IDZ; X-ray; 2.46 A; A=32-505.
DR PDB; 4IE0; X-ray; 2.53 A; A=32-505.
DR PDB; 4IE4; X-ray; 2.50 A; A=32-505.
DR PDB; 4IE5; X-ray; 1.95 A; A=32-505.
DR PDB; 4IE6; X-ray; 2.50 A; A=32-505.
DR PDB; 4IE7; X-ray; 2.60 A; A=32-505.
DR PDBsum; 3LFM; -.
DR PDBsum; 4IDZ; -.
DR PDBsum; 4IE0; -.
DR PDBsum; 4IE4; -.
DR PDBsum; 4IE5; -.
DR PDBsum; 4IE6; -.
DR PDBsum; 4IE7; -.
DR ProteinModelPortal; Q9C0B1; -.
DR SMR; Q9C0B1; 30-503.
DR IntAct; Q9C0B1; 2.
DR STRING; 9606.ENSP00000418823; -.
DR ChEMBL; CHEMBL2331065; -.
DR PhosphoSite; Q9C0B1; -.
DR DMDM; 148841515; -.
DR PaxDb; Q9C0B1; -.
DR PRIDE; Q9C0B1; -.
DR DNASU; 79068; -.
DR Ensembl; ENST00000431610; ENSP00000415636; ENSG00000140718.
DR Ensembl; ENST00000460382; ENSP00000417422; ENSG00000140718.
DR Ensembl; ENST00000463855; ENSP00000417843; ENSG00000140718.
DR Ensembl; ENST00000471389; ENSP00000418823; ENSG00000140718.
DR GeneID; 79068; -.
DR KEGG; hsa:79068; -.
DR UCSC; uc002ehr.3; human.
DR CTD; 79068; -.
DR GeneCards; GC16P053737; -.
DR H-InvDB; HIX0013037; -.
DR H-InvDB; HIX0134382; -.
DR H-InvDB; HIX0204005; -.
DR HGNC; HGNC:24678; FTO.
DR HPA; CAB017123; -.
DR MIM; 610966; gene.
DR MIM; 612938; phenotype.
DR neXtProt; NX_Q9C0B1; -.
DR Orphanet; 210144; Lethal polymalformative syndrome, Boissel type.
DR PharmGKB; PA152208656; -.
DR eggNOG; NOG45792; -.
DR HOGENOM; HOG000273870; -.
DR HOVERGEN; HBG101847; -.
DR InParanoid; Q9C0B1; -.
DR OMA; AVYNYSC; -.
DR OrthoDB; EOG7CK36T; -.
DR PhylomeDB; Q9C0B1; -.
DR ChiTaRS; FTO; human.
DR GeneWiki; FTO_gene; -.
DR GenomeRNAi; 79068; -.
DR NextBio; 67845; -.
DR PRO; PR:Q9C0B1; -.
DR ArrayExpress; Q9C0B1; -.
DR Bgee; Q9C0B1; -.
DR CleanEx; HS_FTO; -.
DR Genevestigator; Q9C0B1; -.
DR GO; GO:0005634; C:nucleus; ISS:BHF-UCL.
DR GO; GO:0043734; F:DNA-N1-methyladenine dioxygenase activity; IDA:UniProtKB.
DR GO; GO:0008198; F:ferrous iron binding; IDA:UniProtKB.
DR GO; GO:0035516; F:oxidative DNA demethylase activity; IDA:UniProtKB.
DR GO; GO:0035515; F:oxidative RNA demethylase activity; IDA:BHF-UCL.
DR GO; GO:0060612; P:adipose tissue development; IEA:Ensembl.
DR GO; GO:0006307; P:DNA dealkylation involved in DNA repair; IDA:UniProtKB.
DR GO; GO:0035552; P:oxidative single-stranded DNA demethylation; IDA:UniProtKB.
DR GO; GO:0035553; P:oxidative single-stranded RNA demethylation; IDA:BHF-UCL.
DR GO; GO:0010883; P:regulation of lipid storage; IEA:Ensembl.
DR GO; GO:0040014; P:regulation of multicellular organism growth; IEA:Ensembl.
DR GO; GO:0044065; P:regulation of respiratory system process; IEA:Ensembl.
DR GO; GO:0070350; P:regulation of white fat cell proliferation; IEA:Ensembl.
DR GO; GO:0042245; P:RNA repair; IDA:BHF-UCL.
DR GO; GO:0001659; P:temperature homeostasis; IEA:Ensembl.
DR InterPro; IPR024366; FTO_C.
DR InterPro; IPR024367; FTO_cat_dom.
DR Pfam; PF12934; FTO_CTD; 1.
DR Pfam; PF12933; FTO_NTD; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Dioxygenase; Disease mutation; DNA damage; DNA repair; Iron;
KW Metal-binding; Nucleus; Obesity; Oxidoreductase; Polymorphism;
KW Reference proteome; RNA repair.
FT CHAIN 1 505 Alpha-ketoglutarate-dependent dioxygenase
FT FTO.
FT /FTId=PRO_0000286163.
FT REGION 32 327 Fe2OG dioxygenase domain.
FT REGION 213 224 Loop L1; predicted to block binding of
FT double-stranded DNA or RNA.
FT REGION 231 234 Substrate binding.
FT REGION 316 318 Alpha-ketoglutarate binding.
FT METAL 231 231 Iron; catalytic.
FT METAL 233 233 Iron; catalytic.
FT METAL 307 307 Iron; catalytic.
FT BINDING 96 96 Substrate.
FT BINDING 108 108 Substrate.
FT BINDING 205 205 Alpha-ketoglutarate.
FT BINDING 295 295 Alpha-ketoglutarate.
FT BINDING 320 320 Alpha-ketoglutarate.
FT BINDING 322 322 Alpha-ketoglutarate.
FT MOD_RES 216 216 N6-acetyllysine.
FT VAR_SEQ 1 445 Missing (in isoform 3).
FT /FTId=VSP_025002.
FT VAR_SEQ 1 399 Missing (in isoform 4).
FT /FTId=VSP_025003.
FT VAR_SEQ 1 378 Missing (in isoform 2).
FT /FTId=VSP_025004.
FT VAR_SEQ 379 413 LRQFWFQGNRYRKCTDWWCQPMAQLEALWKKMEGV -> ME
FT WRKVSECNSVEPCREVKKWPYRCIHHGKNFSRM (in
FT isoform 2).
FT /FTId=VSP_025005.
FT VAR_SEQ 446 455 QNLRREWHAR -> MACQGREECW (in isoform 3).
FT /FTId=VSP_025006.
FT VARIANT 316 316 R -> Q (in GDFD; has no residual normal
FT activity).
FT /FTId=VAR_063252.
FT VARIANT 405 405 A -> V (in dbSNP:rs16952624).
FT /FTId=VAR_032078.
FT MUTAGEN 96 96 R->M,W: Almost abolishes enzyme activity.
FT MUTAGEN 108 108 Y->A: Abolishes enzyme activity.
FT MUTAGEN 114 114 F->D: Perturbs interaction between N-
FT terminal and C-terminal domains and
FT strongly reduces enzyme activity.
FT MUTAGEN 234 234 E->P: Abolishes enzyme activity.
FT MUTAGEN 392 392 C->D: Perturbs interaction between N-
FT terminal and C-terminal domains and
FT strongly reduces enzyme activity.
FT CONFLICT 316 316 R -> W (in Ref. 1; BAB21843 and 3;
FT AAH03583/AAH30798/AAI32893).
FT HELIX 38 45
FT STRAND 49 52
FT HELIX 54 56
FT HELIX 59 74
FT STRAND 79 85
FT STRAND 88 101
FT STRAND 104 108
FT STRAND 111 114
FT HELIX 130 162
FT HELIX 190 196
FT STRAND 201 207
FT TURN 209 211
FT STRAND 212 214
FT STRAND 219 221
FT STRAND 225 231
FT STRAND 242 248
FT STRAND 271 276
FT STRAND 280 282
FT STRAND 284 288
FT STRAND 293 297
FT HELIX 301 304
FT STRAND 305 310
FT STRAND 316 322
FT HELIX 331 342
FT HELIX 361 377
FT HELIX 379 384
FT TURN 385 387
FT HELIX 389 391
FT HELIX 397 422
FT STRAND 423 426
FT HELIX 428 457
FT HELIX 459 463
FT HELIX 466 468
FT STRAND 483 485
FT HELIX 490 500
SQ SEQUENCE 505 AA; 58282 MW; 3498A92C6E6D81B1 CRC64;
MKRTPTAEER EREAKKLRLL EELEDTWLPY LTPKDDEFYQ QWQLKYPKLI LREASSVSEE
LHKEVQEAFL TLHKHGCLFR DLVRIQGKDL LTPVSRILIG NPGCTYKYLN TRLFTVPWPV
KGSNIKHTEA EIAAACETFL KLNDYLQIET IQALEELAAK EKANEDAVPL CMSADFPRVG
MGSSYNGQDE VDIKSRAAYN VTLLNFMDPQ KMPYLKEEPY FGMGKMAVSW HHDENLVDRS
AVAVYSYSCE GPEEESEDDS HLEGRDPDIW HVGFKISWDI ETPGLAIPLH QGDCYFMLDD
LNATHQHCVL AGSQPRFSST HRVAECSTGT LDYILQRCQL ALQNVCDDVD NDDVSLKSFE
PAVLKQGEEI HNEVEFEWLR QFWFQGNRYR KCTDWWCQPM AQLEALWKKM EGVTNAVLHE
VKREGLPVEQ RNEILTAILA SLTARQNLRR EWHARCQSRI ARTLPADQKP ECRPYWEKDD
ASMPLPFDLT DIVSELRGQL LEAKP
//
MIM
610966
*RECORD*
*FIELD* NO
610966
*FIELD* TI
*610966 FAT MASS- AND OBESITY-ASSOCIATED GENE; FTO
;;FATSO, MOUSE, HOMOLOG OF
*FIELD* TX
read more
CLONING
By exon trapping, Peters et al. (1999) cloned a novel gene from a region
of several hundred kb deleted by the mouse 'fused toes' mutation (see
ANIMAL MODEL). They named the gene 'fatso' (Fto) due to its large size.
The predicted 502-amino acid Fto protein has a calculated molecular mass
of 58 kD and contains an N-terminal bipartite nuclear localization
signal. RT-PCR detected Fto expression throughout mouse embryonic
development and in all adult mouse tissues examined except heart and
skin.
Using RT-PCR, Frayling et al. (2007) found that FTO was widely expressed
in a variety of human tissues, with highest levels in brain and
pancreatic islets. Boissel et al. (2009) found ubiquitous expression of
FTO in all human embryo and adult tissues examined, with greatest
expression in the brain and liver. Strong expression was also seen in
the developing heart.
BIOCHEMICAL FEATURES
- Crystal Structure
Han et al. (2010) reported the crystal structure of FTO in complex with
the mononucleotide 3-methylthymidine (3-meT). FTO comprises an
amino-terminal AlkB-like domain and a carboxy-terminal domain with a
novel fold. Biochemical assays showed that these 2 domains interact with
each other, which is required for FTO catalytic activity. In contrast
with the structures of other AlkB members, FTO possesses an extra loop
covering one side of the conserved jelly-roll motif. Structural
comparison showed that this loop selectively competes with the
unmethylated strand of the DNA duplex for binding to FTO, suggesting
that it has an important role in FTO selection against double-stranded
nucleic acids. The ability of FTO to distinguish 3-meT or 3-meU
(methyluracil) from other nucleotides is conferred by its
hydrogen-bonding interaction with the 2 carbonyl oxygen atoms in 3-meT
or 3-meU.
GENE FUNCTION
Gerken et al. (2007) showed by bioinformatics analysis that FTO shares
sequence motifs with iron- and 2-oxoglutarate (2OG)-dependent
oxygenases. They found that recombinant murine Fto catalyzes the iron-
and 2OG-dependent demethylation of 3-methylthymine in single-stranded
DNA, with concomitant production of succinate, formaldehyde, and carbon
dioxide. Consistent with a potential role in nucleic acid demethylation,
Fto localized to the nucleus in transfected cells. Studies of wildtype
mice indicated that Fto mRNA is most abundant in the brain, particularly
in hypothalamic nuclei governing energy balance, and that Fto mRNA
levels in the arcuate nucleus are regulated by feeding and fasting.
MAPPING
Frayling et al. (2007) stated that the FTO gene maps to chromosome 16.
Peters et al. (1999) mapped the mouse Fto gene to chromosome 8.
MOLECULAR GENETICS
For discussion of an association between variation in the FTO gene and
obesity, see BMIQ14 (612460).
In genomewide association studies of type 2 diabetes (125853) involving
genotype data from a variety of international consortia, Zeggini et al.
(2007) and Scott et al. (2007) confirmed FTO as a diabetes
susceptibility locus. Both groups reported evidence of association for
dbSNP rs8050136 (OR = 1.17, P = 1.3 x 10(-12)) in their all-data
metaanalyses.
By genomewide linkage analysis, followed by candidate gene sequencing,
in a consanguineous Palestinian family with severe growth retardation,
developmental delay, coarse facies, and early death (612938), Boissel et
al. (2009) identified a homozygous mutation in the FTO gene (R316Q;
610966.0001).
A risk polymorphism for obesity in the FTO gene, the A allele at dbSNP
rs9939609, has population frequencies of 46% in Western and Central
Europeans, 51% in Yorubans, and 16% in Chinese individuals.
Interestingly, the effect of FTO on BMI may be mediated through impaired
responsiveness to satiety (summary by Ho et al., 2010). Ho et al. (2010)
generated 3D maps of regional brain volume differences in 206 healthy
elderly subjects scanned with MRI and genotyped as part of the
Alzheimer's Disease Neuroimaging Initiative. Ho et al. (2010) found a
pattern of systematic brain volume deficits in carriers of the
obesity-associated risk allele versus noncarriers. Relative to structure
volumes in the mean template, FTO risk allele carriers versus
noncarriers had an average brain volume difference of approximately 8%
in the frontal lobes and 12% in the occipital lobes. These regions also
showed significant volume deficits in subjects with higher BMI. These
brain differences were not attributable to differences in cholesterol
levels, hypertension, or the volume of white matter hyperintensities. Ho
et al. (2010) concluded that these brain maps revealed that a commonly
carried susceptibility allele for obesity is associated with structural
brain atrophy, with implications for the health of the elderly.
Yang et al. (2012) performed a metaanalysis of genomewide association
studies of phenotypic variation using approximately 170,000 samples on
height and BMI in human populations. They reported evidence that the
single-nucleotide polymorphism (SNP) dbSNP 7202116 at the FTO gene
locus, which is known to be associated with obesity, as measured by mean
BMI for each dbSNP rs7202116 genotype, is also associated with
phenotypic variability. The results were not due to scale effects or
other artifacts, and the authors found no experimentwise significant
evidence for effects on variability, either at loci other than FTO for
BMI or at any locus for height. The difference in variance for BMI among
individuals with opposite homozygous genotypes at the FTO locus is
approximately 7%, corresponding to a difference of approximately 0.5 kg
in the standard deviation of weight. Yang et al. (2012) concluded that
genetic variants can be discovered that are associated with variability,
and that between-person variability in obesity can partly be explained
by the genotype at the FTO locus. The authors also concluded that their
BMI results for other SNPs and their height results for all SNPs
suggested that most genetic variants, including those that influence
mean height or mean BMI, are not associated with phenotypic variance, or
that their effects on variability are too small to detect even with
sample sizes greater than 100,000.
ANIMAL MODEL
The mouse fused toes (Ft) mutation was created by insertional
mutagenesis (van der Hoeven et al., 1994), resulting in deletion of
several hundred kb, and likely several genes, on chromosome 8. Ft is a
dominant trait characterized by partial syndactyly of the forelimbs and
massive thymic hyperplasia in heterozygotes. Homozygous Ft/Ft embryos
die at midgestation and show severe malformations of craniofacial
structures and random establishment of left-right asymmetry. Peters et
al. (1999) found that expression of Fto was absent in fibroblasts from
Ft/Ft mice. They concluded that deletion of Fto likely contributes to
the Ft phenotype.
Fischer et al. (2009) generated Fto-null mice and demonstrated that the
loss of Fto in mice leads to postnatal growth retardation and a
significant reduction in adipose tissue and lean body mass. The leanness
of Fto-deficient mice develops as a consequence of increased energy
expenditure and systemic sympathetic activation, despite decreased
spontaneous locomotor activity and relative hyperphagia. Fischer et al.
(2009) concluded that Fto is functionally involved in energy homeostasis
by the control of energy expenditure.
Church et al. (2010) found that transgenic mice expressing 1 or 2
additional copies of the Fto gene exhibited a dose-dependent increase in
body weight and fat mass, particularly females. Transgenic mice
increased their food intake on both standard and high-fat diets, and
they showed reduced glucose tolerance when challenged with a high-fat
diet.
*FIELD* AV
.0001
GROWTH RETARDATION, DEVELOPMENTAL DELAY, COARSE FACIES, AND EARLY
DEATH
FTO, ARG316GLN
In affected members of a consanguineous Palestinian family with growth
retardation, developmental delay, coarse facies, and early death
(612938), Boissel et al. (2009) identified a homozygous 947G-A
transition in the FTO gene, resulting in an arg316-to-gln (R316Q)
substitution in a residue that is conserved across all known paralogs.
The affected residue is involved in 2-oxoglutarate coordination by
forming stabilizing salt bridges with the carboxylates of this
cosubstrate. The mutation was not found in 730 control chromosomes. In
vitro functional expression studies showed that the mutant protein had
no residual normal activity. Cultured skin fibroblasts from 1 patient
showed altered morphology with increased number of vacuoles and cellular
debris and decreased life span, suggesting premature senescence.
*FIELD* RF
1. Boissel, S.; Reish, O.; Proulx, K.; Kawagoe-Takaki, H.; Sedgwick,
B.; Yeo, G. S. H.; Meyre, D.; Golzio, C.; Molinari, F.; Kadhom, N.;
Etchevers, H. C.; Saudek, V.; Farooqi, I. S.; Froguel, P.; Lindahl,
T.; O'Rahilly, S.; Munnich, A.; Colleaux, L.: Loss-of-function mutation
in the dioxygenase-encoding FTO gene causes severe growth retardation
and multiple malformations. Am. J. Hum. Genet. 85: 106-111, 2009.
2. Church, C.; Moir, L.; McMurray, F.; Girard, C.; Banks, G. T.; Teboul,
L.; Wells, S.; Bruning, J. C.; Nolan, P. M.; Ashcroft, F. M.; Cox,
R. D.: Overexpression of Fto leads to increased food intake and results
in obesity. Nature Genet. 42: 1086-1092, 2010.
3. Fischer, J.; Koch, L.; Emmerling, C.; Vierkotten, J.; Peters, T.;
Bruning, J. C.; Ruther, U.: Inactivation of the Fto gene protects
from obesity. Nature 458: 894-898, 2009.
4. Frayling, T. M.; Timpson, N. J.; Weedon, M. N.; Zeggini, E.; Freathy,
R. M.; Lindgren, C. M.; Perry, J. R. B.; Elliott, K. S.; Lango, H.;
Rayner, N. W.; Shields, B.; Harries, L. W.; and 30 others: A common
variant in the FTO gene is associated with body mass index and predisposes
to childhood and adult obesity. Science 316: 889-894, 2007.
5. Gerken, T.; Girard, C. A.; Tung, Y.-C. L.; Webby, C. J.; Saudek,
V.; Hewitson, K. S.; Yeo, G. S. H.; McDonough, M. A.; Cunliffe, S.;
McNeill, L. A.; Galvanovskis, J.; Rorsman, P.; and 13 others: The
obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic
acid demethylase. Science 318: 1469-1472, 2007.
6. Han, Z.; Niu, T.; Chang, J.; Lei, X.; Zhao, M.; Wang, Q.; Cheng,
W.; Wang, J.; Feng, Y.; Chai, J.: Crystal structure of the FTO protein
reveals basis for its substrate specificity. Nature 464: 1205-1209,
2010.
7. Ho, A. J.; Stein, J. L.; Hua, X.; Lee, S.; Hibar, D. P.; Leow,
A. D.; Dinov, I. D.; Toga, A. W.; Saykin, A. J.; Shen, L.; Foroud,
T.; Pankratz, N.; and 17 others: A commonly carried allele of the
obesity-related FTO gene is associated with reduced brain volume in
the healthy elderly. Proc. Nat. Acad. Sci. 107: 8404-8409, 2010.
8. Peters, T.; Ausmeier, K.; Ruther, U.: Cloning of Fatso (Fto),
a novel gene deleted by the Fused toes (Ft) mouse mutation. Mammalian
Genome 10: 983-986, 1999.
9. Scott, L. J.; Mohlke, K. L.; Bonnycastle, L. L.; Willer, C. J.;
Li, Y.; Duren, W. L.; Erdos, M. R.; Stringham, H. M.; Chines, P. S.;
Jackson, A. U.; Prokunina-Olsson, L.; Ding, C.-J.; and 29 others
: A genome-wide association study of type 2 diabetes in Finns detects
multiple susceptibility variants. Science 316: 1341-1345, 2007.
10. van der Hoeven, F.; Schimmang, T.; Volkmann, A.; Mattei, M.-G.;
Kyewski, B.; Ruther, U.: Programmed cell death is affected in the
novel mouse mutant Fused toes (Ft). Development 120: 2601-2607,
1994.
11. Yang, J.; Loos, R. J. F.; Powell, J. E.; Medland, S. E.; Speliotes,
E. K.; Chasman, D. I.; Rose, L. M.; Thorleifsson, G.; Steinthorsdottir,
V.; Magi, R.; Waite, L.; Smith, A. V.; and 160 others: FTO genotype
is associated with phenotypic variability of body mass index. Nature 490:
267-272, 2012.
12. Zeggini, E.; Weedon, M. N.; Lindgren, C. M.; Frayling, T. M.;
Elliott, K. S.; Lango, H.; Timpson, N. J.; Perry, J. R. B.; Rayner,
N. W.; Freathy, R. M.; Barrett, J. C.; Shields, B.; and 15 others
: Replication of genome-wide association signals in UK samples reveals
risk loci for type 2 diabetes. Science 316: 1336-1341, 2007. Note:
Erratum: Science 317: 1036 only, 2007.
*FIELD* CN
Ada Hamosh - updated: 10/25/2012
Ada Hamosh - updated: 6/7/2011
Patricia A. Hartz - updated: 5/16/2011
Ada Hamosh - updated: 5/26/2010
Cassandra L. Kniffin - updated: 7/28/2009
Ada Hamosh - updated: 5/12/2009
Marla J. F. O'Neill - updated: 12/10/2008
Cassandra L. Kniffin - updated: 5/1/2008
Ada Hamosh - updated: 2/14/2008
Marla J. F. O'Neill - updated: 8/6/2007
Ada Hamosh - updated: 7/24/2007
Alan F. Scott - updated: 6/1/2007
*FIELD* CD
Alan F. Scott: 4/24/2007
*FIELD* ED
terry: 11/13/2012
alopez: 11/1/2012
terry: 10/25/2012
alopez: 6/14/2011
terry: 6/7/2011
mgross: 5/16/2011
terry: 5/16/2011
alopez: 6/1/2010
terry: 5/26/2010
alopez: 1/19/2010
terry: 1/15/2010
wwang: 8/11/2009
ckniffin: 7/28/2009
alopez: 5/15/2009
terry: 5/12/2009
carol: 12/10/2008
wwang: 5/14/2008
ckniffin: 5/1/2008
alopez: 2/15/2008
terry: 2/14/2008
carol: 10/10/2007
alopez: 8/6/2007
alopez: 7/27/2007
terry: 7/24/2007
mgross: 6/1/2007
mgross: 4/24/2007
*RECORD*
*FIELD* NO
610966
*FIELD* TI
*610966 FAT MASS- AND OBESITY-ASSOCIATED GENE; FTO
;;FATSO, MOUSE, HOMOLOG OF
*FIELD* TX
read more
CLONING
By exon trapping, Peters et al. (1999) cloned a novel gene from a region
of several hundred kb deleted by the mouse 'fused toes' mutation (see
ANIMAL MODEL). They named the gene 'fatso' (Fto) due to its large size.
The predicted 502-amino acid Fto protein has a calculated molecular mass
of 58 kD and contains an N-terminal bipartite nuclear localization
signal. RT-PCR detected Fto expression throughout mouse embryonic
development and in all adult mouse tissues examined except heart and
skin.
Using RT-PCR, Frayling et al. (2007) found that FTO was widely expressed
in a variety of human tissues, with highest levels in brain and
pancreatic islets. Boissel et al. (2009) found ubiquitous expression of
FTO in all human embryo and adult tissues examined, with greatest
expression in the brain and liver. Strong expression was also seen in
the developing heart.
BIOCHEMICAL FEATURES
- Crystal Structure
Han et al. (2010) reported the crystal structure of FTO in complex with
the mononucleotide 3-methylthymidine (3-meT). FTO comprises an
amino-terminal AlkB-like domain and a carboxy-terminal domain with a
novel fold. Biochemical assays showed that these 2 domains interact with
each other, which is required for FTO catalytic activity. In contrast
with the structures of other AlkB members, FTO possesses an extra loop
covering one side of the conserved jelly-roll motif. Structural
comparison showed that this loop selectively competes with the
unmethylated strand of the DNA duplex for binding to FTO, suggesting
that it has an important role in FTO selection against double-stranded
nucleic acids. The ability of FTO to distinguish 3-meT or 3-meU
(methyluracil) from other nucleotides is conferred by its
hydrogen-bonding interaction with the 2 carbonyl oxygen atoms in 3-meT
or 3-meU.
GENE FUNCTION
Gerken et al. (2007) showed by bioinformatics analysis that FTO shares
sequence motifs with iron- and 2-oxoglutarate (2OG)-dependent
oxygenases. They found that recombinant murine Fto catalyzes the iron-
and 2OG-dependent demethylation of 3-methylthymine in single-stranded
DNA, with concomitant production of succinate, formaldehyde, and carbon
dioxide. Consistent with a potential role in nucleic acid demethylation,
Fto localized to the nucleus in transfected cells. Studies of wildtype
mice indicated that Fto mRNA is most abundant in the brain, particularly
in hypothalamic nuclei governing energy balance, and that Fto mRNA
levels in the arcuate nucleus are regulated by feeding and fasting.
MAPPING
Frayling et al. (2007) stated that the FTO gene maps to chromosome 16.
Peters et al. (1999) mapped the mouse Fto gene to chromosome 8.
MOLECULAR GENETICS
For discussion of an association between variation in the FTO gene and
obesity, see BMIQ14 (612460).
In genomewide association studies of type 2 diabetes (125853) involving
genotype data from a variety of international consortia, Zeggini et al.
(2007) and Scott et al. (2007) confirmed FTO as a diabetes
susceptibility locus. Both groups reported evidence of association for
dbSNP rs8050136 (OR = 1.17, P = 1.3 x 10(-12)) in their all-data
metaanalyses.
By genomewide linkage analysis, followed by candidate gene sequencing,
in a consanguineous Palestinian family with severe growth retardation,
developmental delay, coarse facies, and early death (612938), Boissel et
al. (2009) identified a homozygous mutation in the FTO gene (R316Q;
610966.0001).
A risk polymorphism for obesity in the FTO gene, the A allele at dbSNP
rs9939609, has population frequencies of 46% in Western and Central
Europeans, 51% in Yorubans, and 16% in Chinese individuals.
Interestingly, the effect of FTO on BMI may be mediated through impaired
responsiveness to satiety (summary by Ho et al., 2010). Ho et al. (2010)
generated 3D maps of regional brain volume differences in 206 healthy
elderly subjects scanned with MRI and genotyped as part of the
Alzheimer's Disease Neuroimaging Initiative. Ho et al. (2010) found a
pattern of systematic brain volume deficits in carriers of the
obesity-associated risk allele versus noncarriers. Relative to structure
volumes in the mean template, FTO risk allele carriers versus
noncarriers had an average brain volume difference of approximately 8%
in the frontal lobes and 12% in the occipital lobes. These regions also
showed significant volume deficits in subjects with higher BMI. These
brain differences were not attributable to differences in cholesterol
levels, hypertension, or the volume of white matter hyperintensities. Ho
et al. (2010) concluded that these brain maps revealed that a commonly
carried susceptibility allele for obesity is associated with structural
brain atrophy, with implications for the health of the elderly.
Yang et al. (2012) performed a metaanalysis of genomewide association
studies of phenotypic variation using approximately 170,000 samples on
height and BMI in human populations. They reported evidence that the
single-nucleotide polymorphism (SNP) dbSNP 7202116 at the FTO gene
locus, which is known to be associated with obesity, as measured by mean
BMI for each dbSNP rs7202116 genotype, is also associated with
phenotypic variability. The results were not due to scale effects or
other artifacts, and the authors found no experimentwise significant
evidence for effects on variability, either at loci other than FTO for
BMI or at any locus for height. The difference in variance for BMI among
individuals with opposite homozygous genotypes at the FTO locus is
approximately 7%, corresponding to a difference of approximately 0.5 kg
in the standard deviation of weight. Yang et al. (2012) concluded that
genetic variants can be discovered that are associated with variability,
and that between-person variability in obesity can partly be explained
by the genotype at the FTO locus. The authors also concluded that their
BMI results for other SNPs and their height results for all SNPs
suggested that most genetic variants, including those that influence
mean height or mean BMI, are not associated with phenotypic variance, or
that their effects on variability are too small to detect even with
sample sizes greater than 100,000.
ANIMAL MODEL
The mouse fused toes (Ft) mutation was created by insertional
mutagenesis (van der Hoeven et al., 1994), resulting in deletion of
several hundred kb, and likely several genes, on chromosome 8. Ft is a
dominant trait characterized by partial syndactyly of the forelimbs and
massive thymic hyperplasia in heterozygotes. Homozygous Ft/Ft embryos
die at midgestation and show severe malformations of craniofacial
structures and random establishment of left-right asymmetry. Peters et
al. (1999) found that expression of Fto was absent in fibroblasts from
Ft/Ft mice. They concluded that deletion of Fto likely contributes to
the Ft phenotype.
Fischer et al. (2009) generated Fto-null mice and demonstrated that the
loss of Fto in mice leads to postnatal growth retardation and a
significant reduction in adipose tissue and lean body mass. The leanness
of Fto-deficient mice develops as a consequence of increased energy
expenditure and systemic sympathetic activation, despite decreased
spontaneous locomotor activity and relative hyperphagia. Fischer et al.
(2009) concluded that Fto is functionally involved in energy homeostasis
by the control of energy expenditure.
Church et al. (2010) found that transgenic mice expressing 1 or 2
additional copies of the Fto gene exhibited a dose-dependent increase in
body weight and fat mass, particularly females. Transgenic mice
increased their food intake on both standard and high-fat diets, and
they showed reduced glucose tolerance when challenged with a high-fat
diet.
*FIELD* AV
.0001
GROWTH RETARDATION, DEVELOPMENTAL DELAY, COARSE FACIES, AND EARLY
DEATH
FTO, ARG316GLN
In affected members of a consanguineous Palestinian family with growth
retardation, developmental delay, coarse facies, and early death
(612938), Boissel et al. (2009) identified a homozygous 947G-A
transition in the FTO gene, resulting in an arg316-to-gln (R316Q)
substitution in a residue that is conserved across all known paralogs.
The affected residue is involved in 2-oxoglutarate coordination by
forming stabilizing salt bridges with the carboxylates of this
cosubstrate. The mutation was not found in 730 control chromosomes. In
vitro functional expression studies showed that the mutant protein had
no residual normal activity. Cultured skin fibroblasts from 1 patient
showed altered morphology with increased number of vacuoles and cellular
debris and decreased life span, suggesting premature senescence.
*FIELD* RF
1. Boissel, S.; Reish, O.; Proulx, K.; Kawagoe-Takaki, H.; Sedgwick,
B.; Yeo, G. S. H.; Meyre, D.; Golzio, C.; Molinari, F.; Kadhom, N.;
Etchevers, H. C.; Saudek, V.; Farooqi, I. S.; Froguel, P.; Lindahl,
T.; O'Rahilly, S.; Munnich, A.; Colleaux, L.: Loss-of-function mutation
in the dioxygenase-encoding FTO gene causes severe growth retardation
and multiple malformations. Am. J. Hum. Genet. 85: 106-111, 2009.
2. Church, C.; Moir, L.; McMurray, F.; Girard, C.; Banks, G. T.; Teboul,
L.; Wells, S.; Bruning, J. C.; Nolan, P. M.; Ashcroft, F. M.; Cox,
R. D.: Overexpression of Fto leads to increased food intake and results
in obesity. Nature Genet. 42: 1086-1092, 2010.
3. Fischer, J.; Koch, L.; Emmerling, C.; Vierkotten, J.; Peters, T.;
Bruning, J. C.; Ruther, U.: Inactivation of the Fto gene protects
from obesity. Nature 458: 894-898, 2009.
4. Frayling, T. M.; Timpson, N. J.; Weedon, M. N.; Zeggini, E.; Freathy,
R. M.; Lindgren, C. M.; Perry, J. R. B.; Elliott, K. S.; Lango, H.;
Rayner, N. W.; Shields, B.; Harries, L. W.; and 30 others: A common
variant in the FTO gene is associated with body mass index and predisposes
to childhood and adult obesity. Science 316: 889-894, 2007.
5. Gerken, T.; Girard, C. A.; Tung, Y.-C. L.; Webby, C. J.; Saudek,
V.; Hewitson, K. S.; Yeo, G. S. H.; McDonough, M. A.; Cunliffe, S.;
McNeill, L. A.; Galvanovskis, J.; Rorsman, P.; and 13 others: The
obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic
acid demethylase. Science 318: 1469-1472, 2007.
6. Han, Z.; Niu, T.; Chang, J.; Lei, X.; Zhao, M.; Wang, Q.; Cheng,
W.; Wang, J.; Feng, Y.; Chai, J.: Crystal structure of the FTO protein
reveals basis for its substrate specificity. Nature 464: 1205-1209,
2010.
7. Ho, A. J.; Stein, J. L.; Hua, X.; Lee, S.; Hibar, D. P.; Leow,
A. D.; Dinov, I. D.; Toga, A. W.; Saykin, A. J.; Shen, L.; Foroud,
T.; Pankratz, N.; and 17 others: A commonly carried allele of the
obesity-related FTO gene is associated with reduced brain volume in
the healthy elderly. Proc. Nat. Acad. Sci. 107: 8404-8409, 2010.
8. Peters, T.; Ausmeier, K.; Ruther, U.: Cloning of Fatso (Fto),
a novel gene deleted by the Fused toes (Ft) mouse mutation. Mammalian
Genome 10: 983-986, 1999.
9. Scott, L. J.; Mohlke, K. L.; Bonnycastle, L. L.; Willer, C. J.;
Li, Y.; Duren, W. L.; Erdos, M. R.; Stringham, H. M.; Chines, P. S.;
Jackson, A. U.; Prokunina-Olsson, L.; Ding, C.-J.; and 29 others
: A genome-wide association study of type 2 diabetes in Finns detects
multiple susceptibility variants. Science 316: 1341-1345, 2007.
10. van der Hoeven, F.; Schimmang, T.; Volkmann, A.; Mattei, M.-G.;
Kyewski, B.; Ruther, U.: Programmed cell death is affected in the
novel mouse mutant Fused toes (Ft). Development 120: 2601-2607,
1994.
11. Yang, J.; Loos, R. J. F.; Powell, J. E.; Medland, S. E.; Speliotes,
E. K.; Chasman, D. I.; Rose, L. M.; Thorleifsson, G.; Steinthorsdottir,
V.; Magi, R.; Waite, L.; Smith, A. V.; and 160 others: FTO genotype
is associated with phenotypic variability of body mass index. Nature 490:
267-272, 2012.
12. Zeggini, E.; Weedon, M. N.; Lindgren, C. M.; Frayling, T. M.;
Elliott, K. S.; Lango, H.; Timpson, N. J.; Perry, J. R. B.; Rayner,
N. W.; Freathy, R. M.; Barrett, J. C.; Shields, B.; and 15 others
: Replication of genome-wide association signals in UK samples reveals
risk loci for type 2 diabetes. Science 316: 1336-1341, 2007. Note:
Erratum: Science 317: 1036 only, 2007.
*FIELD* CN
Ada Hamosh - updated: 10/25/2012
Ada Hamosh - updated: 6/7/2011
Patricia A. Hartz - updated: 5/16/2011
Ada Hamosh - updated: 5/26/2010
Cassandra L. Kniffin - updated: 7/28/2009
Ada Hamosh - updated: 5/12/2009
Marla J. F. O'Neill - updated: 12/10/2008
Cassandra L. Kniffin - updated: 5/1/2008
Ada Hamosh - updated: 2/14/2008
Marla J. F. O'Neill - updated: 8/6/2007
Ada Hamosh - updated: 7/24/2007
Alan F. Scott - updated: 6/1/2007
*FIELD* CD
Alan F. Scott: 4/24/2007
*FIELD* ED
terry: 11/13/2012
alopez: 11/1/2012
terry: 10/25/2012
alopez: 6/14/2011
terry: 6/7/2011
mgross: 5/16/2011
terry: 5/16/2011
alopez: 6/1/2010
terry: 5/26/2010
alopez: 1/19/2010
terry: 1/15/2010
wwang: 8/11/2009
ckniffin: 7/28/2009
alopez: 5/15/2009
terry: 5/12/2009
carol: 12/10/2008
wwang: 5/14/2008
ckniffin: 5/1/2008
alopez: 2/15/2008
terry: 2/14/2008
carol: 10/10/2007
alopez: 8/6/2007
alopez: 7/27/2007
terry: 7/24/2007
mgross: 6/1/2007
mgross: 4/24/2007
MIM
612938
*RECORD*
*FIELD* NO
612938
*FIELD* TI
#612938 GROWTH RETARDATION, DEVELOPMENTAL DELAY, COARSE FACIES, AND EARLY
DEATH; GDFD
read more*FIELD* TX
A number sign (#) is used with this entry because the syndrome of severe
growth retardation and developmental delay, coarse facies, and early
death can be caused by homozygous mutation in the FTO gene (610966) on
chromosome 16q12.
CLINICAL FEATURES
Boissel et al. (2009) reported a consanguineous Palestinian Arab family
in which 9 individuals had a severe multiple congenital anomaly syndrome
with death by age 3 years. Clinical features included coarse face with
anteverted nostrils, thin vermilion, prominent alveolar ridge,
retrognathia, and protruding tongue. All had severe failure to thrive in
infancy, and 3 had intrauterine growth retardation. Six patients had
heart defects, including ventricular septal defect, atrioventricular
defect, and patent arteriosus, and 4 had hypertrophic cardiomyopathy.
All showed severe developmental delay and microcephaly variably combined
with lissencephaly, seizures, or Dandy-Walker malformation. Other
features included short neck, brachydactyly, toenail hypoplasia,
neurosensory deafness, umbilical hernia, hypertrophy of the labia,
undescended testes, cleft palate, and optic disc abnormalities. Cultured
skin fibroblasts from 1 patient showed altered morphology with increased
number of vacuoles and cellular debris and decreased life span,
suggesting premature senescence.
MOLECULAR GENETICS
By genomewide linkage analysis, followed by candidate gene sequencing,
in a consanguineous Palestinian family with growth retardation, multiple
congenital anomalies, and early death, Boissel et al. (2009) identified
a homozygous mutation in the FTO gene (R316Q; 610966.0001).
*FIELD* RF
1. Boissel, S.; Reish, O.; Proulx, K.; Kawagoe-Takaki, H.; Sedgwick,
B.; Yeo, G. S. H.; Meyre, D.; Golzio, C.; Molinari, F.; Kadhom, N.;
Etchevers, H. C.; Saudek, V.; Farooqi, I. S.; Froguel, P.; Lindahl,
T.; O'Rahilly, S.; Munnich, A.; Colleaux, L.: Loss-of-function mutation
in the dioxygenase-encoding FTO gene causes severe growth retardation
and multiple malformations. Am. J. Hum. Genet. 85: 106-111, 2009.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Intrauterine growth retardation;
Failure to thrive, severe
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Coarse facies;
Retrognathia;
Prominent alveolar ridge;
[Ears];
Sensorineural deafness;
[Eyes];
Optic disc abnormalities;
[Nose];
Anteverted nostrils;
[Mouth];
Thin vermilion;
Cleft palate;
Bifid uvula;
Protruding tongue;
[Neck];
Short neck
CARDIOVASCULAR:
[Heart];
Ventricular septal defect;
Atrioventricular defect;
Hypertrophic cardiomyopathy;
[Vascular];
Patent ductus arteriosus
GENITOURINARY:
[External genitalia, male];
Genital ambiguity;
[Internal genitalia, male];
Cryptorchidism;
[External genitalia, female];
Genital ambiguity;
Hypertrophy of the labia
SKELETAL:
[Skull];
Skull asymmetry;
[Hands];
Brachydactyly;
Drumstick fingers
SKIN, NAILS, HAIR:
[Skin];
Cutis marmorata;
[Nails];
Toenail hypoplasia
MUSCLE, SOFT TISSUE:
Umbilical hernia
NEUROLOGIC:
[Central nervous system];
Developmental delay, severe;
Hypertonicity;
Hydrocephalus;
Lissencephaly;
Seizures;
Dandy-Walker malformation
MISCELLANEOUS:
Death by age 3 years
MOLECULAR BASIS:
Caused by mutation in the fat mass- and obesity-associated gene (FTO,
610966.0001)
*FIELD* CD
Cassandra L. Kniffin: 7/28/2009
*FIELD* ED
joanna: 10/23/2013
joanna: 7/3/2013
joanna: 1/7/2010
ckniffin: 7/28/2009
*FIELD* CD
Cassandra L. Kniffin: 7/28/2009
*FIELD* ED
carol: 05/24/2011
wwang: 8/11/2009
ckniffin: 7/28/2009
*RECORD*
*FIELD* NO
612938
*FIELD* TI
#612938 GROWTH RETARDATION, DEVELOPMENTAL DELAY, COARSE FACIES, AND EARLY
DEATH; GDFD
read more*FIELD* TX
A number sign (#) is used with this entry because the syndrome of severe
growth retardation and developmental delay, coarse facies, and early
death can be caused by homozygous mutation in the FTO gene (610966) on
chromosome 16q12.
CLINICAL FEATURES
Boissel et al. (2009) reported a consanguineous Palestinian Arab family
in which 9 individuals had a severe multiple congenital anomaly syndrome
with death by age 3 years. Clinical features included coarse face with
anteverted nostrils, thin vermilion, prominent alveolar ridge,
retrognathia, and protruding tongue. All had severe failure to thrive in
infancy, and 3 had intrauterine growth retardation. Six patients had
heart defects, including ventricular septal defect, atrioventricular
defect, and patent arteriosus, and 4 had hypertrophic cardiomyopathy.
All showed severe developmental delay and microcephaly variably combined
with lissencephaly, seizures, or Dandy-Walker malformation. Other
features included short neck, brachydactyly, toenail hypoplasia,
neurosensory deafness, umbilical hernia, hypertrophy of the labia,
undescended testes, cleft palate, and optic disc abnormalities. Cultured
skin fibroblasts from 1 patient showed altered morphology with increased
number of vacuoles and cellular debris and decreased life span,
suggesting premature senescence.
MOLECULAR GENETICS
By genomewide linkage analysis, followed by candidate gene sequencing,
in a consanguineous Palestinian family with growth retardation, multiple
congenital anomalies, and early death, Boissel et al. (2009) identified
a homozygous mutation in the FTO gene (R316Q; 610966.0001).
*FIELD* RF
1. Boissel, S.; Reish, O.; Proulx, K.; Kawagoe-Takaki, H.; Sedgwick,
B.; Yeo, G. S. H.; Meyre, D.; Golzio, C.; Molinari, F.; Kadhom, N.;
Etchevers, H. C.; Saudek, V.; Farooqi, I. S.; Froguel, P.; Lindahl,
T.; O'Rahilly, S.; Munnich, A.; Colleaux, L.: Loss-of-function mutation
in the dioxygenase-encoding FTO gene causes severe growth retardation
and multiple malformations. Am. J. Hum. Genet. 85: 106-111, 2009.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Intrauterine growth retardation;
Failure to thrive, severe
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Coarse facies;
Retrognathia;
Prominent alveolar ridge;
[Ears];
Sensorineural deafness;
[Eyes];
Optic disc abnormalities;
[Nose];
Anteverted nostrils;
[Mouth];
Thin vermilion;
Cleft palate;
Bifid uvula;
Protruding tongue;
[Neck];
Short neck
CARDIOVASCULAR:
[Heart];
Ventricular septal defect;
Atrioventricular defect;
Hypertrophic cardiomyopathy;
[Vascular];
Patent ductus arteriosus
GENITOURINARY:
[External genitalia, male];
Genital ambiguity;
[Internal genitalia, male];
Cryptorchidism;
[External genitalia, female];
Genital ambiguity;
Hypertrophy of the labia
SKELETAL:
[Skull];
Skull asymmetry;
[Hands];
Brachydactyly;
Drumstick fingers
SKIN, NAILS, HAIR:
[Skin];
Cutis marmorata;
[Nails];
Toenail hypoplasia
MUSCLE, SOFT TISSUE:
Umbilical hernia
NEUROLOGIC:
[Central nervous system];
Developmental delay, severe;
Hypertonicity;
Hydrocephalus;
Lissencephaly;
Seizures;
Dandy-Walker malformation
MISCELLANEOUS:
Death by age 3 years
MOLECULAR BASIS:
Caused by mutation in the fat mass- and obesity-associated gene (FTO,
610966.0001)
*FIELD* CD
Cassandra L. Kniffin: 7/28/2009
*FIELD* ED
joanna: 10/23/2013
joanna: 7/3/2013
joanna: 1/7/2010
ckniffin: 7/28/2009
*FIELD* CD
Cassandra L. Kniffin: 7/28/2009
*FIELD* ED
carol: 05/24/2011
wwang: 8/11/2009
ckniffin: 7/28/2009