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16  structures 125  species 1  interaction 222  sequences 5  architectures

Family: FTO_NTD (PF12933)

Summary: FTO catalytic domain

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "FTO gene". More...

FTO gene Edit Wikipedia article

Available structures
PDB Ortholog search: PDBe RCSB
Aliases FTO, ALKBH9, GDFD, BMIQ14, fat mass and obesity associated, alpha-ketoglutarate dependent dioxygenase
External IDs OMIM: 610966 MGI: 1347093 HomoloGene: 8053 GeneCards: FTO
Gene location (Human)
Chromosome 16 (human)
Chr. Chromosome 16 (human)[1]
Chromosome 16 (human)
Genomic location for FTO
Genomic location for FTO
Band 16q12.2 Start 53,701,692 bp[1]
End 54,158,512 bp[1]
RNA expression pattern
PBB GE FTO 209702 at fs.png

PBB GE FTO gnf1h06407 at fs.png
More reference expression data
Species Human Mouse
RefSeq (mRNA)



RefSeq (protein)


Location (UCSC) Chr 16: 53.7 – 54.16 Mb Chr 8: 91.31 – 91.67 Mb
PubMed search [3] [4]
View/Edit Human View/Edit Mouse

Fat mass and obesity-associated protein also known as alpha-ketoglutarate-dependent dioxygenase FTO is an enzyme that in humans is encoded by the FTO gene located on chromosome 16. As one homolog in the AlkB family proteins, it is the first mRNA demethylase that has been identified.[5] Certain variants of the FTO gene appear to be correlated with obesity in humans.[6]


The amino acid sequence of the transcribed FTO protein shows high similarity with the enzyme AlkB which oxidatively demethylates DNA.[7][8] FTO is a member of the superfamily of alpha-ketoglutarate-dependent hydroxylase, which are non-heme iron-containing proteins. Recombinant FTO protein was first discovered to catalyze demethylation of 3-methylthymine in single-stranded DNA, and 3-methyluridine in single-stranded RNA, with low efficiency.[7] The nucleoside N6-methyladenosine, an abundant modification in RNA, was then found to be a major substrate of FTO.[5][9] The FTO gene expression was also found to be significantly upregulated in the hypothalamus of rats after food deprivation and strongly negatively correlated with the expression of orexigenic galanin-like peptide which is involved in the stimulation of food intake.[10]

Increases in hypothalamic expression of FTO are associated with the regulation of energy intake but not feeding reward.[11]

People with two copies of the risk allele for the rs9939609 single nucleotide polymorphism (SNP) showed differing neural responses to food images via fMRI.[12] However, rs9939609's association with FTO is controversial, and may actually affect another gene, called iroquious homeobox protein 3 (IRX3).[13]

FTO demethylates RNA

N6-methyladenosine (m6A) is an abundant modification in mRNA and is found within some viruses,[14][15] and most eukaryotes including mammals,[16][17][18][19] insects,[20] plants,[21][22][23] and yeast.[24][25] It is also found in tRNA, rRNA, and small nuclear RNA (snRNA) as well as several long non-coding RNA, such as Xist.[9][26] Adenosine methylation is directed by a large m6A methyltransferase complex containing METTL3 as the SAM-binding sub-unit.[27] In vitro, this methyltransferase complex preferentially methylates RNA oligonucleotides containing GGACU[28] and a similar preference was identified in vivo in mapped m6A sites in Rous sarcoma virus genomic RNA[29] and in bovine prolactin mRNA.[30] In plants, the majority of the m6A is found within 150 nucleotides before the start of the poly(A) tail.[31]

Mapping of m6A in human and mouse RNA has identified over 18,000 m6A sites in the transcripts of more than 7,000 human genes with a consensus sequence of [G/A/U][G>A]m6AC[U>A/C][9][26] consistent with the previously identified motif.[28] Sites preferentially appear in two distinct landmarks—around stop codons and within long internal exons—and are highly conserved between human and mouse.[9][26] A subset of stimulus-dependent, dynamically modulated sites has been identified. Silencing the m6A methyltransferase significantly affects gene expression and alternative RNA splicing patterns, resulting in modulation of the p53 (also known as TP53) signalling pathway and apoptosis.

FTO has been demonstrated to efficiently demethylate the related modified ribonucleotide, N6,2'-O-dimethyladenosine, and to an equal or lesser extent, m6A, in vitro .[5][32] FTO knockdown with siRNA led to increased amounts of m6A in polyA-RNA, whereas overexpression of FTO resulted in decreased amounts of m6A in human cells.[9] FTO partially co-localizes with nuclear speckles, which supports the notion that in the nucleus, m6A can be a substrate of FTO. Function of FTO could affect the processing of pre-mRNA, other nuclear RNAs, or both. The discovery of the FTO-mediated oxidative demethylation of RNA may initiate further investigations on biological regulation based on reversible chemical modification of RNA, and identification of RNA substrates for which FTO has the highest affinity.[5][9][32]

Tissue distribution

The FTO gene is widely expressed in both fetal and adult tissues.[33]

Clinical significance

Association with obesity

Fat Mass and Obesity-Associated (FTO) Protein

38,759 Europeans were studied for variants of FTO obesity risk allele.[33] In particular, carriers of one copy of the allele weighed on average 1.2 kilograms (2.6 lb) more than people with no copies. Carriers of two copies (16% of the subjects) weighed 3 kilograms (6.6 lb) more and had a 1.67-fold higher rate of obesity than those with no copies. The association was observed in ages 7 and upwards. This gene is not directly associated with diabetes; however, increased body-fat also increases the risk of developing type 2 diabetes.[34]

Simultaneously, a study in 2,900 affected individuals and 5,100 controls of French descent, together with 500 trios (confirming an association independent of population stratification) found association of SNPs in the very same region of FTO (rs1421085).[35] The authors found that this variation, or a variation in strong LD with this variation explains 1% of the population BMI variance and 22% of the population attributable risk of obesity. The authors of this study claim that while obesity was already known to have a genetic component (from twin studies), no replicated previous study has ever identified an obesity risk allele that was so common in the human population. The risk allele is a cluster of 10 single nucleotide polymorphism in the first intron of FTO called rs9939609. According to HapMap, it has population frequencies of 45% in the West/Central Europeans, 52% in Yorubans (West African natives) and 14% in Chinese/Japanese. Furthermore, morbid obesity is associated with a combination of FTO and INSIG2 single nucleotide polymorphisms.[36]

In 2009, variants in the FTO gene were further confirmed to associate with obesity in two very large genome wide association studies of body mass index (BMI).[37][38]

In adult humans, it was shown that adults bearing the at risk AT and AA alleles at rs9939609 consumed between 500 and 1250 kJ more each day than those carrying the protective TT genotype (equivalent to between 125 and 280 kcal per day more intake).[39] The same study showed that there was no impact of the polymorphism on energy expenditure. This finding of an effect of the rs9939609 polymorphism on food intake or satiety has been independently replicated in five subsequent studies (in order of publication).[40][41][42][43][44] Three of these subsequent studies also measured resting energy expenditure and confirmed the original finding that there is no impact of the polymorphic variation at the rs9939609 locus on energy expenditure. A different study explored the effects of variation in two different SNPs in the FTO gene (rs17817449 and rs1421085) and suggested there might be an effect on circulating leptin levels and energy expenditure, but this latter effect disappeared when the expenditure was normalised for differences in body composition.[45] The accumulated data across seven independent studies therefore clearly implicates the FTO gene in humans as having a direct impact on food intake but no effect on energy expenditure.

The obesity-associated noncoding region within the FTO gene interacts directly with the promoter of IRX3, a homeobox gene, and IRX5, another homeobox gene. The noncoding region of FTO interacts with the promoters of IRX3 and FTO in human, mouse and zebrafish, and with IRX5. Results suggest that IRX3 and IRX5 are linked with obesity and determine body mass and composition. This is further supported by the fact that obesity-associated single nucleotide polymorphisms, in which cytosine is substituted for thymine, are involved in the expression of IRX3 and IRX5 (not FTO) in human brains. The enhanced expression of IRX3 and IRX5 resulting from this single nucleotide alteration promoted a shift from energy-dissipating beige adipocytes to energy-storing white adipocytes and a subsequent reduction in mitochondrial thermogenesis by a factor of 5.[46][47] Another study found indications that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner, and that there is a pathway for adipocyte thermoregulation which involves the proteine ARID5B, the single-nucleotide variant rs1421085, and the IRX3 and IRX5 genes.[48]

Association with Alzheimer's disease

Recent studies revealed that carriers of common FTO gene polymorphisms show both a reduction in frontal lobe volume of the brain[49] and an impaired verbal fluency performance.[50] Fittingly, a population-based study from Sweden found that carriers of the FTO rs9939609 A allele have an increased risk for incident Alzheimer disease.[51]

Association with other diseases

The presence of the FTO rs9939609 A allele was also found to be positively correlated with other symptoms of the metabolic syndrome, including higher fasting insulin, glucose, and triglycerides, and lower HDL cholesterol. However all these effects appear to be secondary to weight increase since no association was found after correcting for increases in body mass index.[52] Similarly, the association of rs11076008 G allele with the increased risk for degenerative disc disease was reported.[53]

Model organisms

Model organisms have been used in the study of FTO function. In contrast to the findings in humans deletion, analysis of the Fto gene in mice showed loss of function is associated with no differences in energy intake but greater energy expenditure and this results in a reduction of body weight and fatness.[54]

Another conditional knockout mouse line, called Ftotm1a(EUCOMM)Wtsi[60][61] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[62][63][64] Male and female animals from this line underwent a standardized phenotypic screen to determine the effects of deletion.[58][65] Twenty five tests were carried out on mutant mice and only significant skeletal abnormalities were observed, including kyphosis and abnormal vertebral transverse processes, and only in female homozygous mutant animals.[58]

The reasons for the differences in FTO phenotype between humans and different lines of mice is presently uncertain. However, many other genes involved in regulation of energy balance exert effects on both intake and expenditure.

Origin of name

By exon trapping, Peters et al. (1999) cloned a novel gene from a region of several hundred kb deleted by the mouse 'fused toes' (FT) mutation. They named the gene 'fatso' (Fto) due to its large size.[66][67]


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External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

FTO catalytic domain Provide feedback

This domain is the catalytic AlkB-like domain from the FTO protein [1]. This domain catalyses a demethylase activity with a preference for 3-methylthymidine.

Literature references

  1. Han Z, Niu T, Chang J, Lei X, Zhao M, Wang Q, Cheng W, Wang J, Feng Y, Chai J;, Nature. 2010; [Epub ahead of print]: Crystal structure of the FTO protein reveals basis for its substrate specificity. PUBMED:20376003 EPMC:20376003

Internal database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR024367

Alpha-ketoglutarate-dependent dioxygenase FTO, also known as Fat mass and obesity-associated protein, is a nucleus protein which belongs to the FTO family. This enzyme is a dioxygenase that repairs alkylated DNA and RNA by oxidative demethylation [PUBMED:17991826]. FTO activity is highest towards single-stranded RNA containing 3-methyluracil, followed by single-stranded DNA containing 3-methylthymine. FTO has low demethylase activity towards single-stranded DNA containing 1-methyladenine or 3-methylcytosine [PUBMED:18775698]. FTO has no activity towards 1-methylguanine. It has no detectable activity towards double-stranded DNA. FTO requires molecular oxygen, alpha-ketoglutarate and iron. FTO contributes to the regulation of the global metabolic rate, energy expenditure and energy homeostasis. It contributes to the regulation of body size and body fat accumulation as well [PUBMED:19234441].

This domain is the catalytic AlkB-like domain from the FTO protein [PUBMED:20376003]. This domain catalyses a demethylase activity with a preference for 3-methylthymidine.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

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Representative proteomes UniProt

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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...


This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Jackhmmer:Q9C0B1
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: Bateman A
Number in seed: 18
Number in full: 222
Average length of the domain: 265.10 aa
Average identity of full alignment: 56 %
Average coverage of the sequence by the domain: 61.08 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 27.0 10.0
Trusted cut-off 28.9 16.3
Noise cut-off 26.3 9.9
Model length: 286
Family (HMM) version: 7
Download: download the raw HMM for this family

Species distribution

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Archea Archea Eukaryota Eukaryota
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Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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There is 1 interaction for this family. More...



For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the FTO_NTD domain has been found. There are 16 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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