Prevalence of Loss-of-Function FTO Mutations in Lean and Obese Individuals
- David Meyre1,
- Karine Proulx2,
- Hiroko Kawagoe-Takaki3,
- Vincent Vatin1,
- Ruth Gutiérrez-Aguilar1,
- Debbie Lyon3,
- Marcella Ma2,
- Helene Choquet1,
- Fritz Horber4,
- Wim Van Hul5,
- Luc Van Gaal6,
- Beverley Balkau7,
- Sophie Visvikis-Siest8,
- François Pattou9,
- I. Sadaf Farooqi2,
- Vladimir Saudek2,
- Stephen O'Rahilly2,
- Philippe Froguel1,10,
- Barbara Sedgwick3 and
- Giles S.H. Yeo2
- 1CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France;
- 2University of Cambridge Metabolic Research Labs, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.;
- 3Cancer Research U.K. London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire, U.K.;
- 4Klinik Lindberg, Winterthur, and University of Berne, Berne, Switzerland;
- 5Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium;
- 6Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Edegem, Belgium;
- 7INSERM U780, Villejuif, France, and University Paris-Sud, Orsay, France;
- 8INSERM “Cardiovascular Genetics” team, Nancy, France;
- 9INSERM U859, CHRU Lille, Lille North of France University, Lille, France;
- 10Section of Genomic Medicine, Hammersmith Hospital, Imperial College London, London, U.K.
- Corresponding author: Giles Yeo, gshy2{at}cam.ac.uk.
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D.M., K.P., and H.K.-T. contributed equally to this work.
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.
RESEARCH DESIGN AND 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.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Received May 11, 2009.
- Accepted September 24, 2009.
- © 2010 American Diabetes Association
