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Prevalence of Mutations and Functional Analyses of Melanocortin 4 Receptor Variants Identified among 750 Men with Juvenile-Onset Obesity

Steno Diabetes Center and Hagedorn Research Institute (L.H.L., S.M.E., O.P.), 2820 Gentofte, Denmark; Exiqon (S.M.E.), 2950 Vedbaek, Denmark; Danish Epidemiology Science Centre (L.H.L., T.I.A.S.), Institute of Preventive Medicine, Copenhagen University Hospital, 1357 Copenhagen, Denmark; Roskilde County Hospital (T.A.), University of Copenhagen, 4000 Roskilde, Denmark; Department of Molecular Pharmacology (B.S.W.), Novo Nordisk, 2760 Maaloev, Denmark; and Faculty of Health Science (O.P.), University of Aarhus, 8000 Aarhus, Denmark

Address all correspondence and requests for reprints to: Lesli Hingstrup Larsen, Steno Diabetes Center and Hagedorn Research Institute, Niels Steensens Vej 6, NSK 1.14, 2820 Gentofte, Denmark. E-mail: LieL{at}Steno.dk.

Mutations in the gene encoding the melanocortin 4 receptor (MC4R) are associated with the most common monogenic form of obesity. We examined 750 Danish men with juvenile-onset obesity (body mass index 33.3 ± 2.4 kg/m²) and 706 control subjects (body mass index 21.4 ± 2.1 kg/m²) for mutations in MC4R. A total of 14 different mutations were identified of which two, Ala219Val and Leu325Phe, were novel variants. The variant receptor, Leu325Phe, was unable to bind [Nle4,D-Phe7]-MSH, whereas the Ala219Val variant showed a significantly impaired melanotan II induction of cAMP, compared with the wild-type receptor. The remaining 11 mutations have previously been reported, but selected MC4R variants were further characterized in vitro in the present study. A previously identified nonsense mutation, Tyr35stop, had a relatively high allele frequency (0.6%), suggesting a possible founder effect in the Danish population. This study shows a carrier frequency of 2.5% of pathogenic mutations in the MC4R gene in a population-based study of obese men. Thus, variation in this gene is the most common known specific genetic cause of obesity among Scandinavian men.

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