title: Prevalence of loss-of-function FTO mutations in lean and obese individuals.
abstract: OBJECTIVE
  Single nucleotide polymorphisms (SNPs) in intron 1 of fat mass- and obesity-associated gene (FTO) are strongly associated with human adiposity, whereas Fto(-/-) mice are lean and Fto(+/-) mice are resistant to diet-induced obesity. We aimed to determine whether FTO mutations are disproportionately represented in lean or obese humans and to use these mutations to understand structure-function relationships within FTO.
  
  
  METHODS
  We sequenced all coding exons of FTO in 1,433 severely obese and 1,433 lean individuals. We studied the enzymatic activity of selected nonsynonymous variants.
  
  
  RESULTS
  We identified 33 heterozygous nonsynonymous variants in lean (2.3%) and 35 in obese (2.4%) individuals, with 8 mutations unique to the obese and 11 unique to the lean. Two novel mutations replace absolutely conserved residues: R322Q in the catalytic domain and R96H in the predicted substrate recognition lid. R322Q was unable to catalyze the conversion of 2-oxoglutarate to succinate in the presence or absence of 3-methylthymidine. R96H retained some basal activity, which was not enhanced by 3-methylthymidine. However, both were found in lean and obese individuals.
  
  
  CONCLUSIONS
  Heterozygous, loss-of-function mutations in FTO exist but are found in both lean and obese subjects. Although intron 1 SNPs are unequivocally associated with obesity in multiple populations and murine studies strongly suggest that FTO has a role in energy balance, it appears that loss of one functional copy of FTO in humans is compatible with being either lean or obese. Functional analyses of FTO mutations have given novel insights into structure-function relationships in this enzyme.
authors.affiliation: CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France.
authors.forename: David
authors.initials: D
authors.lastname: Meyre
authors.forename: Karine
authors.initials: K
authors.lastname: Proulx
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kawagoe-Takaki
authors.forename: Vincent
authors.initials: V
authors.lastname: Vatin
authors.forename: Ruth
authors.initials: R
authors.lastname: Gutiérrez-Aguilar
authors.forename: Debbie
authors.initials: D
authors.lastname: Lyon
authors.forename: Marcella
authors.initials: M
authors.lastname: Ma
authors.forename: Helene
authors.initials: H
authors.lastname: Choquet
authors.forename: Fritz
authors.initials: F
authors.lastname: Horber
authors.forename: Wim
authors.initials: W
authors.lastname: Van Hul
authors.forename: Luc
authors.initials: L
authors.lastname: Van Gaal
authors.forename: Beverley
authors.initials: B
authors.lastname: Balkau
authors.forename: Sophie
authors.initials: S
authors.lastname: Visvikis-Siest
authors.forename: François
authors.initials: F
authors.lastname: Pattou
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
authors.forename: Vladimir
authors.initials: V
authors.lastname: Saudek
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Barbara
authors.initials: B
authors.lastname: Sedgwick
authors.forename: Giles S H
authors.initials: GS
authors.lastname: Yeo
mesh_terms: D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D019943:Amino Acid Substitution; D005091:Exons; D006801:Humans; D007438:Introns; D009154:Mutation; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D012016:Reference Values; D013851:Thinness / Q000235:genetics*
chemical_list: D011506:Proteins; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human