title: Obesity-associated mutations in the melanocortin 4 receptor provide novel insights into its function.
abstract: Mutations in the Melanocortin 4 receptor are implicated in 1-6% of early onset or severe adult obesity cases. Most of the patients carry heterozygous missense mutations. Arguments for the pathogenicity of these mutations are based on the frequency of rare functionally relevant non-synonymous mutations in severely obese children and adults versus non-obese controls, the segregation of mutations with obesity in the family of the probands (although with incomplete penetrance) and the relevant functional defects described for these mutations. We have developed new assays to study the functional characteristics of these obesity-associated MC4R mutations. Systematic and comparative functional study of over 50 different obesity-associated mutations suggests that multiple functional alterations contribute to their pathogenicity. These studies also lead to new insights into the structure-function relationship of MC4R, provide novel hypotheses for the genetic predisposition to common obesity in humans and allow the development of new molecular tools for studying the physiological role of GPCRs.
authors.affiliation: Cellular and Molecular Pharmacology Department, University of California, San Francisco, CA 94143, USA.
authors.forename: Cedric
authors.initials: C
authors.lastname: Govaerts
authors.forename: Supriya
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Astrid
authors.initials: A
authors.lastname: Shapiro
authors.forename: Sumei
authors.initials: S
authors.lastname: Zhang
authors.forename: Franck
authors.initials: F
authors.lastname: Picard
authors.forename: Karine
authors.initials: K
authors.lastname: Clement
authors.forename: Cecile
authors.initials: C
authors.lastname: Lubrano-Berthelier
authors.forename: Christian
authors.initials: C
authors.lastname: Vaisse
mesh_terms: D000818:Animals; D006801:Humans; D016296:Mutagenesis / Q000502:physiology; D009765:Obesity / Q000235:genetics* / Q000378:metabolism*; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D044105:Receptor, Melanocortin, Type 4