FTO

This gene is a nuclear protein of the AlkB related non-haem iron and 2-oxoglutarate-dependent oxygenase superfamily but the exact physiological function of this gene is not known. Other non-heme iron enzymes function to reverse alkylated DNA and RNA damage by oxidative demethylation. Studies in mice and humans indicate a role in nervous and cardiovascular systems and a strong association with body mass index, obesity risk, and type 2 diabetes. [provided by RefSeq, Jul 2011]

FTO, Alpha-Ketoglutarate Dependent Dioxygenase

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 N6-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 N6,2'-O-dimethyladenosine cap (m6A(m)), by demethylating the N6-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 N1-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).

Adipose tissue development Source: Ensembl
DNA dealkylation involved in DNA repair Source: UniProtKB
DNA demethylation Source: BHF-UCL
mRNA destabilization Source: UniProtKB
Oxidative demethylation Source: BHF-UCL
Oxidative single-stranded DNA demethylation Source: UniProtKB
Oxidative single-stranded RNA demethylation Source: UniProtKB
Regulation of brown fat cell differentiation Source: UniProtKB
Regulation of lipid storage Source: UniProtKB
Regulation of multicellular organism growth Source: Ensembl
Regulation of respiratory system process Source: Ensembl
Regulation of white fat cell proliferation Source: Ensembl
RNA repair Source: BHF-UCL
Temperature homeostasis Source: Ensembl

Nucleus; Nucleus speckle; Cytoplasm. Localizes mainly in the nucleus, where it is able to demethylate N6-methyladenosine (m6A) and N6,2'-O-dimethyladenosine cap (m6A(m)) in U6 small nuclear RNA (snRNA), N1-methyladenine from tRNAs and internal m6A in mRNAs (PubMed:30197295). In the cytoplasm, mediates demethylation of m6A and m6A(m) in mRNAs and N1-methyladenine from tRNAs (PubMed:30197295).

Growth retardation, developmental delay, and facial dysmorphism (GDFD):
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.
Obesity (OBESITY):
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). 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.