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Genetic Screening for Melanocortin-4 Receptor Mutations in a Cohort of Italian Obese Patients: Description and Functional Characterization of a Novel Mutation

Department of Endocrinology and Metabolism (F.S., G.C., C.P., G.S., V.R., A.M., S.L., M.T., P.A., C.M., P.V., A.P.), and Dulbecco Telethon Institute at Department of Endocrinology and Metabolism (M.M., C.C.), University of Pisa, 56124 Pisa, Italy; and Endocrinology Unit, University of Pavia, Fondazione Salvatore Maugeri Istituto di Ricovero e Cura a Carattere Scientifico (L.C.), 27100 Pavia, Italy

Address all correspondence and requests for reprints to: Ferruccio Santini, M.D., Department of Endocrinology, University of Pisa, Via Paradisa, 2, 56124 Pisa, Italy. E-mail: fsantini{at}endoc.med.unipi.it.

Mutations in the human melanocortin-4 receptor (MC4-R) gene may account for up to 5.8% of morbid nonsyndromic obesity. We have screened 120 unrelated obese patients for variants of the MC4-R gene. Four heterozygous missense variants were detected, including two polymorphisms (Val¹⁰³Ile and Ile²⁵¹Leu) previously described in the literature. A novel heterozygous mutation (Glu³⁰⁸Lys) was detected in a 36-yr-old female patient. Compared with the wild-type receptor, cells expressing the mutated receptor showed a reduced stimulation of cAMP production and a reduction of radioactive MSH binding. No segregation of the mutation with the obese phenotype could be demonstrated. A second, potentially pathogenic mutation (Ser³⁰Phe) was detected in a 31-yr-old female patient. Functional analysis of the mutated receptor showed no change in the affinity to the natural ligand MSH nor limited ability to stimulate cAMP production. Sixty lean subjects were also screened, and no additional variants of the MC4-R gene were observed, except for two individuals with the Val¹⁰³Ile polymorphism. In conclusion, we have screened a population of Italian obese subjects for MC4-R variants, demonstrating a 1.7% prevalence of potentially pathogenic mutations. A novel heterozygous missense mutation (Glu³⁰⁸Lys) that impairs MC4-R functional activity in vitro was characterized.

This work was supported by the following grants: Ministero dell’Istruzione, dell’Università e della Ricerca Scientifica, Programmi di Ricerca Cofinanziati 2002: Obesity: Phenotype Characterization and Relationship with Pathogenesis; Ministero della Salute, Programma Speciale di Sperimentazione Spprovato nell’Anno 2000: Strategia Multidisciplinare per la Prevenzione e la Cura dell’Obesità e dei Disturbi del Comportamento Alimentare; Ministero dell’Istruzione, dell’Università e della Ricerca Scientifica, Centro di Eccellenza AmbiSEN: Effects of Envinromental Chemical Agents on the Endocrine and Nervous System; Telethon Foundation Contract Grant TCP99016 (to M.M.); a Telethon Fellowship (to C.C.), and an Assistant Telethon Scientist Award (to M.M.).

Abbreviations: BMI, Body mass index; MC4-R, melanocortin-4 receptor.

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