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Submitted on June 27, 2005
Accepted on February 16, 2006
Diabetes Center and Department of Medicine, University of California San Francisco, San Francisco CA 94143; Inserm Avenir, 75004 Paris, France; University Pierre et Marie Curie-Paris 6, EA3502, IFR58, 75004 Paris, France; CHRU Pitié Salpétrière, Centre de Recherche en Nutrition Humaine Ile de de France, Hôtel-Dieu 75004 Paris, France; Inserm Avenir, 75004 Paris, France; University Pierre et Marie Curie-Paris 6, EA3502, IFR58, 75004 Paris, France; Department of Pediatric Gastroenterology and Nutrition, Armand-Trousseau Teaching Hospital, Paris, France; Biochemistry Department, Hôtel-Dieu Hospital, Paris, France; UMR INSERM unit 557/INRA unit 1125, Institut Scientifique et Technique de la Nutrition et de l'Alimentation, ISTNA-CNAM, Paris, France
* To whom correspondence should be addressed. E-mail: vaisse{at}medicine.ucsf.edu.
Context: Heterozygous mutations in the melanocortin-4 receptor (MC4R) gene are the most common monogenic form of severe obesity in children. There are conflicting reports regarding the prevalence, nature and pathogenic effects of MC4R mutations in adults with severe late-onset obesity.
Objective: To determine the prevalence of MC4R mutations in a cohort of severely obese adults. To determine the clinical phenotype and the phenotype-genotype relationship within adult MC4R mutation carriers.
Design: Observational study.
Setting: Referral center.
Patients or other participants: 769 adult patients with BMI
35kg/m2 and 444 non-obese control individuals.
Interventions: None
Main outcome measures: Prevalence of pathogenic MC4R mutations, functional characteristics of the detected mutations, phenotype and phenotype-genotype relationship within mutation carriers.
Results: The global prevalence of obesity specific MC4R mutations was 2.6%, CI95 [1.5-3.7]. The prevalence of MC4R mutations was similar in patients developing obesity in childhood (2.83%, CI95 [0.9 -4.8] and in patients with a later onset of the disease (2.35%, CI95 [0.9-3.8]). Adult obese MC4R mutation carriers did not present with binge eating nor with any specific clinical phenotype. The severity of the functional alterations of the mutated MC4Rs and in particular the intracellular retention of the receptor correlates both with the severity and the onset of the obesity in the mutation carriers.
Conclusions: Obese adult carriers of functionally relevant MC4R mutations do not specifically present with binge eating disorder or a history of early-onset obesity. The onset and severity of the obesity in the carriers is related to the functional severity of the MC4R mutations.
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