title: Genetic screening for melanocortin-4 receptor mutations in a cohort of Italian obese patients: description and functional characterization of a novel mutation.
abstract: 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 (Val(103)Ile and Ile(251)Leu) previously described in the literature. A novel heterozygous mutation (Glu(308)Lys) 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 alpha MSH binding. No segregation of the mutation with the obese phenotype could be demonstrated. A second, potentially pathogenic mutation (Ser(30)Phe) 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 alpha 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 Val(103)Ile 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 (Glu(308)Lys) that impairs MC4-R functional activity in vitro was characterized.
authors.affiliation: Department of Endocrinology and Metabolism, University of Pisa, 56124 Pisa, Italy. fsantini@endoc.med.unipi.it
authors.forename: Ferruccio
authors.initials: F
authors.lastname: Santini
authors.forename: Margherita
authors.initials: M
authors.lastname: Maffei
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ceccarini
authors.forename: Caterina
authors.initials: C
authors.lastname: Pelosini
authors.forename: Giovanna
authors.initials: G
authors.lastname: Scartabelli
authors.forename: Veronica
authors.initials: V
authors.lastname: Rosellini
authors.forename: Chiara
authors.initials: C
authors.lastname: Chiellini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Marsili
authors.forename: Simonetta
authors.initials: S
authors.lastname: Lisi
authors.forename: Massimo
authors.initials: M
authors.lastname: Tonacchera
authors.forename: Patrizia
authors.initials: P
authors.lastname: Agretti
authors.forename: Luca
authors.initials: L
authors.lastname: Chiovato
authors.forename: Claudia
authors.initials: C
authors.lastname: Mammoli
authors.forename: Paolo
authors.initials: P
authors.lastname: Vitti
authors.forename: Aldo
authors.initials: A
authors.lastname: Pinchera
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002648:Child; D002522:Chlorocebus aethiops; D015331:Cohort Studies; D005260:Female; D005820:Genetic Testing; D018698:Glutamic Acid / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007558:Italy; D008239:Lysine / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics / Q000502:physiology; D020125:Mutation, Missense; D009765:Obesity / Q000235:genetics*; D010375:Pedigree; D010649:Phenylalanine / Q000235:genetics; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*; D012694:Serine / Q000235:genetics
chemical_list: D044105:Receptor, Melanocortin, Type 4; D018698:Glutamic Acid; D012694:Serine; D010649:Phenylalanine; D008239:Lysine