UniProt functional annotation for Q9C0B1



	UniProt functional annotation for Q9C0B1

UniProt code: Q9C0B1.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: RNA demethylase that mediates oxidative demethylation of different RNA species, such as mRNAs, tRNAs and snRNAs, and acts as a regulator of fat mass, adipogenesis and energy homeostasis (PubMed:22002720, PubMed:26458103, PubMed:28002401, PubMed:30197295, PubMed:26457839, PubMed:25452335). Specifically demethylates N(6)- methyladenosine (m6A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes (PubMed:22002720, PubMed:26458103, PubMed:30197295, PubMed:26457839, PubMed:25452335). M6A demethylation by FTO affects mRNA expression and stability (PubMed:30197295). Also able to demethylate m6A in U6 small nuclear RNA (snRNA) (PubMed:30197295). Mediates demethylation of N(6),2'-O- dimethyladenosine cap (m6A(m)), by demethylating the N(6)- methyladenosine at the second transcribed position of mRNAs and U6 snRNA (PubMed:28002401, PubMed:30197295). Demethylation of m6A(m) in the 5'-cap by FTO affects mRNA stability by promoting susceptibility to decapping (PubMed:28002401). Also acts as a tRNA demethylase by removing N(1)-methyladenine from various tRNAs (PubMed:30197295). Has no activity towards 1-methylguanine (PubMed:20376003). Has no detectable activity towards double-stranded DNA (PubMed:20376003). Also able to repair alkylated DNA and RNA by oxidative demethylation: demethylates single-stranded RNA containing 3-methyluracil, single- stranded DNA containing 3-methylthymine and has low demethylase activity towards single-stranded DNA containing 1-methyladenine or 3- methylcytosine (PubMed:18775698, PubMed:20376003). Ability to repair alkylated DNA and RNA is however unsure in vivo (PubMed:18775698, PubMed:20376003). Involved in the regulation of fat mass, adipogenesis and body weight, thereby contributing to the regulation of body size and body fat accumulation (PubMed:18775698, PubMed:20376003). Involved in the regulation of thermogenesis and the control of adipocyte differentiation into brown or white fat cells (PubMed:26287746). Regulates activity of the dopaminergic midbrain circuitry via its ability to demethylate m6A in mRNAs (By similarity). Plays an oncogenic role in a number of acute myeloid leukemias by enhancing leukemic oncogene-mediated cell transformation: acts by mediating m6A demethylation of target transcripts such as MYC, CEBPA, ASB2 and RARA, leading to promote their expression (PubMed:28017614, PubMed:29249359). {ECO:0000250|UniProtKB:Q8BGW1, ECO:0000269|PubMed:18775698, ECO:0000269|PubMed:20376003, ECO:0000269|PubMed:22002720, ECO:0000269|PubMed:25452335, ECO:0000269|PubMed:26287746, ECO:0000269|PubMed:26457839, ECO:0000269|PubMed:26458103, ECO:0000269|PubMed:28002401, ECO:0000269|PubMed:28017614, ECO:0000269|PubMed:29249359, ECO:0000269|PubMed:30197295}.

Catalytic activity: Reaction=2-oxoglutarate + a 5'-end (N(7)-methyl 5'- triphosphoguanosine)-(N(6),2'-O-dimethyladenosine) in mRNA + O2 = a 5'-end (N(7)-methyl 5'-triphosphoguanosine)-(2'-O-methyladenosine) in mRNA + CO2 + formaldehyde + succinate; Xref=Rhea:RHEA:57896, Rhea:RHEA-COMP:11518, Rhea:RHEA-COMP:11519, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:85958, ChEBI:CHEBI:85959; Evidence={ECO:0000269|PubMed:28002401, ECO:0000269|PubMed:30197295};

Catalytic activity: Reaction=2-oxoglutarate + N(6)-methyladenosine in mRNA + O2 = adenosine in mRNA + CO2 + formaldehyde + succinate; Xref=Rhea:RHEA:49520, Rhea:RHEA-COMP:12414, Rhea:RHEA-COMP:12417, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:74411, ChEBI:CHEBI:74449; EC=1.14.11.53; Evidence={ECO:0000269|PubMed:25452335, ECO:0000269|PubMed:26457839, ECO:0000269|PubMed:30197295, ECO:0000305|PubMed:22002720};

Catalytic activity: Reaction=2-oxoglutarate + N(6)-methyladenosine in U6 snRNA + O2 = adenosine in U6 snRNA + CO2 + formaldehyde + succinate; Xref=Rhea:RHEA:57900, Rhea:RHEA-COMP:13573, Rhea:RHEA-COMP:13574, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:74411, ChEBI:CHEBI:74449; Evidence={ECO:0000269|PubMed:30197295};

Catalytic activity: Reaction=2-oxoglutarate + a 5'-end (N(7)-methyl 5'- triphosphoguanosine)-(N(6),2'-O-dimethyladenosine) in U6 snRNA + O2 = a 5'-end (N(7)-methyl 5'-triphosphoguanosine)-(2'-O-methyladenosine) in U6 snRNA + CO2 + formaldehyde + succinate; Xref=Rhea:RHEA:57904, Rhea:RHEA-COMP:15030, Rhea:RHEA-COMP:15031, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:85958, ChEBI:CHEBI:85959; Evidence={ECO:0000269|PubMed:30197295};

Catalytic activity: Reaction=2-oxoglutarate + an N(1)-methyladenosine in tRNA + O2 = an adenosine in tRNA + CO2 + formaldehyde + succinate; Xref=Rhea:RHEA:54576, Rhea:RHEA-COMP:10242, Rhea:RHEA-COMP:12312, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:74411, ChEBI:CHEBI:74491; Evidence={ECO:0000269|PubMed:30197295};

Cofactor: Name=Fe(2+); Xref=ChEBI:CHEBI:29033; Evidence={ECO:0000269|PubMed:20376003}; Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000269|PubMed:20376003};

Activity regulation: Activated by ascorbate (By similarity). Inhibited by N-oxalylglycine, fumarate and succinate (By similarity). RNA N(6)- methyladenosine demethylase activity is inhibited by fluorescein derivatives (PubMed:26457839). RNA N(6)-methyladenosine demethylase activity is selectively inhibited by meclofenamic acid; inhibition is specific to FTO and meclofenamic acid does not inhibit ALKBH5 (PubMed:25452335). Specifically inhibited by R-2-hydroxyglutarate (R- 2HG), an oncometabolite that also exerts a broad antileukemic activity (PubMed:29249359). Inhibition by R-2HG leads to increased level of N(6)-methyladenosine-containing transcripts, leading to down-regulate expression of MYC and CEBPA transcripts (PubMed:29249359). {ECO:0000250|UniProtKB:Q8BGW1, ECO:0000269|PubMed:25452335, ECO:0000269|PubMed:26457839, ECO:0000269|PubMed:29249359}.

Biophysicochemical properties: Kinetic parameters: KM=1.34 uM for m(7)Gppp(m6A(m))CA mRNA {ECO:0000269|PubMed:28002401}; KM=16.09 uM for m(7)Gppp(m6ACA mRNA {ECO:0000269|PubMed:28002401}; KM=9.29 uM for GG(m6A)CU mRNA {ECO:0000269|PubMed:28002401}; KM=6.4 uM for m(7)GpppAC(m6) mRNA {ECO:0000269|PubMed:28002401}; Note=Kcat is 8.78 min(-1) for m(7)Gppp(m6A(m))CA mRNA. Kcat is 7.77 min(-1) for m(7)Gppp(m6A)CA mRNA. Kcat is 0.54 min(-1) for GG(m6A)CU mRNA. Kcat is 0.46 min(-1) for m(7)GpppAC(m6) mRNA. {ECO:0000269|PubMed:28002401}; pH dependence: Optimum pH is 5.5-6. {ECO:0000269|PubMed:18775698};

Subunit: Monomer (By similarity). May also exist as homodimer (By similarity). {ECO:0000250|UniProtKB:Q8BGW1}.

Subcellular location: Nucleus {ECO:0000269|PubMed:22002720, ECO:0000269|PubMed:26458103, ECO:0000269|PubMed:28002401, ECO:0000269|PubMed:30197295}. Nucleus speckle {ECO:0000269|PubMed:22002720}. Cytoplasm {ECO:0000269|PubMed:30197295}. Note=Localizes mainly in the nucleus, where it is able to demethylate N(6)-methyladenosine (m6A) and N(6),2'-O-dimethyladenosine cap (m6A(m)) in U6 small nuclear RNA (snRNA), N(1)-methyladenine from tRNAs and internal m6A in mRNAs (PubMed:30197295). In the cytoplasm, mediates demethylation of m6A and m6A(m) in mRNAs and N(1)-methyladenine from tRNAs (PubMed:30197295). {ECO:0000269|PubMed:30197295}.

Tissue specificity: Ubiquitously expressed, with relatively high expression in adrenal glands and brain; especially in hypothalamus and pituitary (PubMed:17434869, PubMed:17496892). Highly expressed in highly expressed in acute myeloid leukemias (AML) with t(11;11)(q23;23) with KMT2A/MLL1 rearrangements, t(15;17)(q21;q21)/PML-RARA, FLT3-ITD, and/or NPM1 mutations (PubMed:28017614). {ECO:0000269|PubMed:17434869, ECO:0000269|PubMed:17496892, ECO:0000269|PubMed:28017614}.

Domain: The 3D-structure of the Fe2OG dioxygenase domain is similar to that of the Fe2OG dioxygenase domain found in the bacterial DNA repair dioxygenase alkB and its mammalian orthologs, but sequence similarity is very low. As a consequence, the domain is not detected by protein signature databases. {ECO:0000269|PubMed:20376003}.

Polymorphism: Genetic variations at the FTO locus define the body mass index quantitative trait locus 14 (BMIQ14) [MIM:612460]. Variance in body mass index is a susceptibility factor for obesity. {ECO:0000269|PubMed:17434869, ECO:0000269|PubMed:17496892, ECO:0000269|PubMed:22982992}.

Disease: Growth retardation, developmental delay, and facial dysmorphism (GDFD) [MIM:612938]: A severe polymalformation syndrome characterized by postnatal growth retardation, microcephaly, severe psychomotor delay, functional brain deficits and characteristic facial dysmorphism. In some patients, structural brain malformations, cardiac defects, genital anomalies, and cleft palate are observed. Early death occurs by the age of 3 years. {ECO:0000269|PubMed:19559399, ECO:0000269|PubMed:22002720, ECO:0000269|PubMed:26378117, ECO:0000269|PubMed:26697951}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Obesity (OBESITY) [MIM:601665]: A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. {ECO:0000269|PubMed:24646999, ECO:0000269|PubMed:26287746}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry. It is unclear whether variations associated with obesity directly affect FTO function or alter the expression of adjacent genes such as IRX3, rather than FTO itself (PubMed:24646999, PubMed:26287746). A pathogenic intronic FTO variation (rs1421085) disrupts an evolutionarily conserved motif for ARID5B binding (PubMed:26287746). Loss of ARID5B binding results in overexpression of two genes distal to FTO, IRX3 and IRX5. IRX3 and IRX5 overexpression shifts pre-adipocytes differentiation from brown to white fat cells, resulting in increased lipid storage and loss of mitochondrial thermogenesis (PubMed:26287746). {ECO:0000269|PubMed:24646999, ECO:0000269|PubMed:26287746}.

Similarity: Belongs to the fto family. {ECO:0000305}.

Sequence caution: Sequence=BAB21843.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		RNA demethylase that mediates oxidative demethylation of different RNA species, such as mRNAs, tRNAs and snRNAs, and acts as a regulator of fat mass, adipogenesis and energy homeostasis (PubMed:22002720, PubMed:26458103, PubMed:28002401, PubMed:30197295, PubMed:26457839, PubMed:25452335). Specifically demethylates N(6)- methyladenosine (m6A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes (PubMed:22002720, PubMed:26458103, PubMed:30197295, PubMed:26457839, PubMed:25452335). M6A demethylation by FTO affects mRNA expression and stability (PubMed:30197295). Also able to demethylate m6A in U6 small nuclear RNA (snRNA) (PubMed:30197295). Mediates demethylation of N(6),2'-O- dimethyladenosine cap (m6A(m)), by demethylating the N(6)- methyladenosine at the second transcribed position of mRNAs and U6 snRNA (PubMed:28002401, PubMed:30197295). Demethylation of m6A(m) in the 5'-cap by FTO affects mRNA stability by promoting susceptibility to decapping (PubMed:28002401). Also acts as a tRNA demethylase by removing N(1)-methyladenine from various tRNAs (PubMed:30197295). Has no activity towards 1-methylguanine (PubMed:20376003). Has no detectable activity towards double-stranded DNA (PubMed:20376003). Also able to repair alkylated DNA and RNA by oxidative demethylation: demethylates single-stranded RNA containing 3-methyluracil, single- stranded DNA containing 3-methylthymine and has low demethylase activity towards single-stranded DNA containing 1-methyladenine or 3- methylcytosine (PubMed:18775698, PubMed:20376003). Ability to repair alkylated DNA and RNA is however unsure in vivo (PubMed:18775698, PubMed:20376003). Involved in the regulation of fat mass, adipogenesis and body weight, thereby contributing to the regulation of body size and body fat accumulation (PubMed:18775698, PubMed:20376003). Involved in the regulation of thermogenesis and the control of adipocyte differentiation into brown or white fat cells (PubMed:26287746). Regulates activity of the dopaminergic midbrain circuitry via its ability to demethylate m6A in mRNAs (By similarity). Plays an oncogenic role in a number of acute myeloid leukemias by enhancing leukemic oncogene-mediated cell transformation: acts by mediating m6A demethylation of target transcripts such as MYC, CEBPA, ASB2 and RARA, leading to promote their expression (PubMed:28017614, PubMed:29249359). {ECO:0000250\|UniProtKB:Q8BGW1, ECO:0000269\|PubMed:18775698, ECO:0000269\|PubMed:20376003, ECO:0000269\|PubMed:22002720, ECO:0000269\|PubMed:25452335, ECO:0000269\|PubMed:26287746, ECO:0000269\|PubMed:26457839, ECO:0000269\|PubMed:26458103, ECO:0000269\|PubMed:28002401, ECO:0000269\|PubMed:28017614, ECO:0000269\|PubMed:29249359, ECO:0000269\|PubMed:30197295}.


Catalytic activity:		Reaction=2-oxoglutarate + a 5'-end (N(7)-methyl 5'- triphosphoguanosine)-(N(6),2'-O-dimethyladenosine) in mRNA + O2 = a 5'-end (N(7)-methyl 5'-triphosphoguanosine)-(2'-O-methyladenosine) in mRNA + CO2 + formaldehyde + succinate; Xref=Rhea:RHEA:57896, Rhea:RHEA-COMP:11518, Rhea:RHEA-COMP:11519, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:85958, ChEBI:CHEBI:85959; Evidence={ECO:0000269\|PubMed:28002401, ECO:0000269\|PubMed:30197295};
Catalytic activity:		Reaction=2-oxoglutarate + N(6)-methyladenosine in mRNA + O2 = adenosine in mRNA + CO2 + formaldehyde + succinate; Xref=Rhea:RHEA:49520, Rhea:RHEA-COMP:12414, Rhea:RHEA-COMP:12417, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:74411, ChEBI:CHEBI:74449; EC=1.14.11.53; Evidence={ECO:0000269\|PubMed:25452335, ECO:0000269\|PubMed:26457839, ECO:0000269\|PubMed:30197295, ECO:0000305\|PubMed:22002720};
Catalytic activity:		Reaction=2-oxoglutarate + N(6)-methyladenosine in U6 snRNA + O2 = adenosine in U6 snRNA + CO2 + formaldehyde + succinate; Xref=Rhea:RHEA:57900, Rhea:RHEA-COMP:13573, Rhea:RHEA-COMP:13574, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:74411, ChEBI:CHEBI:74449; Evidence={ECO:0000269\|PubMed:30197295};
Catalytic activity:		Reaction=2-oxoglutarate + a 5'-end (N(7)-methyl 5'- triphosphoguanosine)-(N(6),2'-O-dimethyladenosine) in U6 snRNA + O2 = a 5'-end (N(7)-methyl 5'-triphosphoguanosine)-(2'-O-methyladenosine) in U6 snRNA + CO2 + formaldehyde + succinate; Xref=Rhea:RHEA:57904, Rhea:RHEA-COMP:15030, Rhea:RHEA-COMP:15031, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:85958, ChEBI:CHEBI:85959; Evidence={ECO:0000269\|PubMed:30197295};
Catalytic activity:		Reaction=2-oxoglutarate + an N(1)-methyladenosine in tRNA + O2 = an adenosine in tRNA + CO2 + formaldehyde + succinate; Xref=Rhea:RHEA:54576, Rhea:RHEA-COMP:10242, Rhea:RHEA-COMP:12312, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:74411, ChEBI:CHEBI:74491; Evidence={ECO:0000269\|PubMed:30197295};
Cofactor:		Name=Fe(2+); Xref=ChEBI:CHEBI:29033; Evidence={ECO:0000269\|PubMed:20376003}; Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000269\|PubMed:20376003};
Activity regulation:		Activated by ascorbate (By similarity). Inhibited by N-oxalylglycine, fumarate and succinate (By similarity). RNA N(6)- methyladenosine demethylase activity is inhibited by fluorescein derivatives (PubMed:26457839). RNA N(6)-methyladenosine demethylase activity is selectively inhibited by meclofenamic acid; inhibition is specific to FTO and meclofenamic acid does not inhibit ALKBH5 (PubMed:25452335). Specifically inhibited by R-2-hydroxyglutarate (R- 2HG), an oncometabolite that also exerts a broad antileukemic activity (PubMed:29249359). Inhibition by R-2HG leads to increased level of N(6)-methyladenosine-containing transcripts, leading to down-regulate expression of MYC and CEBPA transcripts (PubMed:29249359). {ECO:0000250\|UniProtKB:Q8BGW1, ECO:0000269\|PubMed:25452335, ECO:0000269\|PubMed:26457839, ECO:0000269\|PubMed:29249359}.
Biophysicochemical properties:		Kinetic parameters: KM=1.34 uM for m(7)Gppp(m6A(m))CA mRNA {ECO:0000269\|PubMed:28002401}; KM=16.09 uM for m(7)Gppp(m6ACA mRNA {ECO:0000269\|PubMed:28002401}; KM=9.29 uM for GG(m6A)CU mRNA {ECO:0000269\|PubMed:28002401}; KM=6.4 uM for m(7)GpppAC(m6) mRNA {ECO:0000269\|PubMed:28002401}; Note=Kcat is 8.78 min(-1) for m(7)Gppp(m6A(m))CA mRNA. Kcat is 7.77 min(-1) for m(7)Gppp(m6A)CA mRNA. Kcat is 0.54 min(-1) for GG(m6A)CU mRNA. Kcat is 0.46 min(-1) for m(7)GpppAC(m6) mRNA. {ECO:0000269\|PubMed:28002401}; pH dependence: Optimum pH is 5.5-6. {ECO:0000269\|PubMed:18775698};
Subunit:		Monomer (By similarity). May also exist as homodimer (By similarity). {ECO:0000250\|UniProtKB:Q8BGW1}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:22002720, ECO:0000269\|PubMed:26458103, ECO:0000269\|PubMed:28002401, ECO:0000269\|PubMed:30197295}. Nucleus speckle {ECO:0000269\|PubMed:22002720}. Cytoplasm {ECO:0000269\|PubMed:30197295}. Note=Localizes mainly in the nucleus, where it is able to demethylate N(6)-methyladenosine (m6A) and N(6),2'-O-dimethyladenosine cap (m6A(m)) in U6 small nuclear RNA (snRNA), N(1)-methyladenine from tRNAs and internal m6A in mRNAs (PubMed:30197295). In the cytoplasm, mediates demethylation of m6A and m6A(m) in mRNAs and N(1)-methyladenine from tRNAs (PubMed:30197295). {ECO:0000269\|PubMed:30197295}.
Tissue specificity:		Ubiquitously expressed, with relatively high expression in adrenal glands and brain; especially in hypothalamus and pituitary (PubMed:17434869, PubMed:17496892). Highly expressed in highly expressed in acute myeloid leukemias (AML) with t(11;11)(q23;23) with KMT2A/MLL1 rearrangements, t(15;17)(q21;q21)/PML-RARA, FLT3-ITD, and/or NPM1 mutations (PubMed:28017614). {ECO:0000269\|PubMed:17434869, ECO:0000269\|PubMed:17496892, ECO:0000269\|PubMed:28017614}.
Domain:		The 3D-structure of the Fe2OG dioxygenase domain is similar to that of the Fe2OG dioxygenase domain found in the bacterial DNA repair dioxygenase alkB and its mammalian orthologs, but sequence similarity is very low. As a consequence, the domain is not detected by protein signature databases. {ECO:0000269\|PubMed:20376003}.
Polymorphism:		Genetic variations at the FTO locus define the body mass index quantitative trait locus 14 (BMIQ14) [MIM:612460]. Variance in body mass index is a susceptibility factor for obesity. {ECO:0000269\|PubMed:17434869, ECO:0000269\|PubMed:17496892, ECO:0000269\|PubMed:22982992}.
Disease:		Growth retardation, developmental delay, and facial dysmorphism (GDFD) [MIM:612938]: A severe polymalformation syndrome characterized by postnatal growth retardation, microcephaly, severe psychomotor delay, functional brain deficits and characteristic facial dysmorphism. In some patients, structural brain malformations, cardiac defects, genital anomalies, and cleft palate are observed. Early death occurs by the age of 3 years. {ECO:0000269\|PubMed:19559399, ECO:0000269\|PubMed:22002720, ECO:0000269\|PubMed:26378117, ECO:0000269\|PubMed:26697951}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Obesity (OBESITY) [MIM:601665]: A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. {ECO:0000269\|PubMed:24646999, ECO:0000269\|PubMed:26287746}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry. It is unclear whether variations associated with obesity directly affect FTO function or alter the expression of adjacent genes such as IRX3, rather than FTO itself (PubMed:24646999, PubMed:26287746). A pathogenic intronic FTO variation (rs1421085) disrupts an evolutionarily conserved motif for ARID5B binding (PubMed:26287746). Loss of ARID5B binding results in overexpression of two genes distal to FTO, IRX3 and IRX5. IRX3 and IRX5 overexpression shifts pre-adipocytes differentiation from brown to white fat cells, resulting in increased lipid storage and loss of mitochondrial thermogenesis (PubMed:26287746). {ECO:0000269\|PubMed:24646999, ECO:0000269\|PubMed:26287746}.
Similarity:		Belongs to the fto family. {ECO:0000305}.
Sequence caution:		Sequence=BAB21843.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};