Prevalence of loss-of-function FTO mutations in lean and obese individuals.
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.
Meyre
David
D
CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France.
Proulx
Karine
K
Kawagoe-Takaki
Hiroko
H
Vatin
Vincent
V
Gutiérrez-Aguilar
Ruth
R
Lyon
Debbie
D
Ma
Marcella
M
Choquet
Helene
H
Horber
Fritz
F
Van Hul
Wim
W
Van Gaal
Luc
L
Balkau
Beverley
B
Visvikis-Siest
Sophie
S
Pattou
François
F
Farooqi
I Sadaf
IS
Saudek
Vladimir
V
O'Rahilly
Stephen
S
Froguel
Philippe
P
Sedgwick
Barbara
B
Yeo
Giles S H
GS
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*
D011506:Proteins; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human