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A Homozygous Null Mutation Delineates the Role of the Melanocortin-4 Receptor in Humans

Department of Medicine, Division of Endocrinology and Diabetes Center, University of California (C.L.-B, C.V.), San Francisco, California 94143-0573; and Institut National de la Santé et de la Recherche Médicale, Unité 561, Department of Pediatric Endocrinology, Saint Vincent de Paul Hospital, University René Descartes (C.L.S., P.B.), Paris, France

Address all correspondence and requests for reprints to: Dr. Christian Vaisse, Diabetes Center, University of California, 513 Parnassus Avenue, Box 0573, San Francisco, California 94143-0573. E-mail: vaisse{at}medicine.ucsf.edu.

As a mediator of the effects of leptin, the melanocortin-4 receptor (MC4R) is an essential component of the central regulation of long-term energy homeostasis. Heterozygous mutations in this receptor are the most frequent genetic cause of severe obesity in children. The very rare described carriers of homozygous MC4R mutations for whom clinical data were available had a residual receptor activity thus not allowing for the description of the full extent of the role of MC4R in humans. Here, we present the clinical and biological features of a patient with complete absence of MC4R activity and compare the clinical and endocrine characteristics of this patient with those previously observed in leptin receptor-deficient patients. Our data suggest that in humans, the MC4R mediates most of the anorectic effects of leptin in early childhood. In contrast, MC4R does not mediate the effect of leptin on linear growth and other endocrine axes. In addition, complete MC4R deficiency is not a cause of relative hyperinsulinemia as recently observed in children with heterozygous MC4R mutations.

This work was supported by National Institutes of Health Grant RO1-DK-60540 and an American Diabetes Association Career Development Award (to C.V.).

Abbreviations: AGRP, Agouti-related peptide; BMI, body mass index; LEPR, leptin receptor; MC4R, melanocortin-4 receptor; NPY, neuropeptide Y; RFLP, restriction fragment length polymorphism.

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