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Identification and Characterization of Melanocortin-4 Receptor Gene Mutations in Morbidly Obese Finnish Children and Adults

Department of Medicine and Research Program in Molecular Medicine (K.V.-J., L.O., K.K., C.S.-J.), University of Helsinki, FIN-00290 Helsinki, Finland; The Hospital for Children and Adolescents (M.L.-N.) and Department of Endocrinology (C.S.-J.), Helsinki University Hospital, FIN-00290 Helsinki, Finland; and Department of Medicine (A.N.H., C.B.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Camilla Schalin-Jäntti, M.D., Ph.D., Departments of Medicine and Endocrinology, Helsinki University Hospital, Haartmaninkatu 4, P.O. Box 340, FIN-00290 Helsinki, Finland. E-mail: camilla.schalin-jantti{at}hus.fi.

Two Finnish cohorts, comprising 56 children with severe early-onset obesity (relative weight for height greater than or equal to +70% before age 10) and 252 morbidly obese adults (body mass index, 40 kg/m²), were screened for melanocortin-4 receptor (MC4R) mutations. We identified a pathogenic mutation (S127L) in one child, causing severe early-onset obesity. We describe the phenotype of this particular mutation for the first time. We also identified a novel (I226T) polymorphism in the coding and two new variations (-439delGC and 1059C>T) outside the coding region of the MC4R gene. Three previously described polymorphisms (V103I, T112M, and I125L) were identified. In vitro functional studies of variants T112M, S127L, and I226T supported a pathogenic role of the S127L mutation, because signaling properties of the receptor in response to the MC4R agonists -MSH, ß-MSH, and ₁-MSH were impaired. The S127L mutation did not affect receptor inhibition by the antagonist agouti-related protein. Localization of the three variant receptors was similar to that of wild type. In conclusion, a pathogenic MC4R mutation was found among subjects with severe early-onset obesity but not among morbidly obese adults. Impaired function of the S127L receptor was due to reduced activation, not a defect of protein transport to the cell membrane.

This work was supported by grants from Finska Läkaresällskapet (to K.V.-J.), the Sigrid Juselius Foundation (to K.V.-J., L.O., and K.K.), the National Institutes of Health (RO1 DK60673) (to C.B.), the Research Funds from the University Central Hospital in Helsinki (to M.L.-N. and C.S.-J.), the Finnish Academy (to K.K.), the Emil Aaltonen Foundation (to L.O.), and the Finnish Foundation for Cardiovascular Research (to L.O. and K.K.).

Abbreviations: AGRP, Agouti-related protein; BMI, body mass index; ß-gal, ß-galactosidase; GFP, green fluorescent protein; h, human; HA, hemagglutinin; MC4R, melanocortin-4 receptor; OGTT, oral glucose tolerance test; wt, wild type.

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