Identification and Characterization of Melanocortin-4 Receptor Gene Mutations in Morbidly Obese Finnish Children and Adults
Kaisa Valli-Jaakola,
Marita Lipsanen-Nyman,
Laura Oksanen,
Anthony N. Hollenberg,
Kimmo Kontula,
Christian Bjørbæk and
Camilla Schalin-Jäntti
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-onsetobesity (relative weight for height greater than or equal to+70% before age 10) and 252 morbidly obese adults (body massindex, 40 kg/m2), were screened for melanocortin-4receptor (MC4R) mutations. We identified a pathogenic mutation(S127L) in one child, causing severe early-onset obesity. Wedescribe the phenotype of this particular mutation for the firsttime. We also identified a novel (I226T) polymorphism in thecoding and two new variations (-439delGC and 1059C>T) outsidethe coding region of the MC4R gene. Three previously describedpolymorphisms (V103I, T112M, and I125L) were identified. Invitro functional studies of variants T112M, S127L, and I226Tsupported a pathogenic role of the S127L mutation, because signalingproperties of the receptor in response to the MC4R agonists-MSH, ß-MSH, and 1-MSH were impaired. The S127L mutationdid not affect receptor inhibition by the antagonist agouti-relatedprotein. Localization of the three variant receptors was similarto that of wild type. In conclusion, a pathogenic MC4R mutationwas found among subjects with severe early-onset obesity butnot among morbidly obese adults. Impaired function of the S127Lreceptor was due to reduced activation, not a defect of proteintransport 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) (toC.B.), the Research Funds from the University Central Hospitalin Helsinki (to M.L.-N. and C.S.-J.), the Finnish Academy (toK.K.), the Emil Aaltonen Foundation (to L.O.), and the FinnishFoundation for Cardiovascular Research (to L.O. and K.K.).
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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. 
