Human Molecular Genetics

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Human Molecular Genetics, 2003, Vol. 12, No. 2 145-153
© 2003 Oxford University Press

Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations

Cecile Lubrano-Berthelier¹, Emmanuelle Durand², Beatrice Dubern^1,3, Astrid Shapiro¹, Paul Dazin⁴, Jacques Weill⁵, Camille Ferron¹, Philippe Froguel^2,6 and Christian Vaisse^1,*

¹Diabetes Center and Department of Medicine, University of California, San Francisco, CA 94143, USA, ²CNRS 80-90-Institute of Biology of Lille, Institute Pasteur, Lille, France, ³Pediatric Gastroenterology and Nutrition Department, Armand-Trousseau Teaching Hospital, Paris, France, ⁴Howard Hughes Medical Institute, ⁵Department of Pediatrics, Lille University Hospital, Lille, France and ⁶Barts and The London Genome Center, Queen Mary School of Medicine, London, UK

Received September 17, 2002; Accepted November 13, 2002

Heterozygous mutations in the coding region of the serpentine Melanocortin 4 receptor are the most common genetic cause of human obesity described to date. There are still conflicting data regarding the overall prevalence of such mutations in obesity and limited information is available on the functional defects caused by most obesity-associated MC4R mutations. We report here the screening for mutations in the coding region of the MC4R of a new cohort of 172 patients presenting with severe childhood obesity and a family history of obesity. Three heterozygous MC4R mutations (Ser127Leu, Ala244Glu and Pro299His) were found in three patients of this cohort (1.74%), confirming that such mutations are implicated in a significant number of childhood obesity cases. A functional analysis of these mutant receptors, in addition to 11 other childhood obesity-associated MC4R mutations, indicates that they all alter the activation of the receptor by the endogenous agonist -MSH. To further examine the functional defects caused by childhood obesity-associated MC4R mutations, we developed a novel, sensitive technique to quantitatively analyze the effect of a mutation on MC4R cell surface expression. Using this method we analyzed the cell surface expression of all the 14 described childhood obesity-associated MC4R missense mutations. We demonstrate that 81.3% of childhood obesity-associated heterozygous MC4R mutations lead to intracellular retention of the receptor. This result has implications for the potential pharmacologic rescue of childhood obesity-associated MC4R mutations and for the treatment of patients presenting with this condition.

^* To whom correspondence should be addressed at: University of California, San Francisco, Diabetes Center and Department of Medicine, Room HSW1113, 513 Parnassus Avenue, San Francisco, CA 94143-0573, USA. Tel: +1 4155140530; Fax: +1 4155645813; Email: vaisse{at}medicine.ucsf.edu

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