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Deletion of Codons 88–92 of the Melanocortin-4 Receptor Gene: A Novel Deleterious Mutation in an Obese Female

Departments of Pediatrics (P.A.D., M.C.) and Physiology and Biophysics (Y.-X.T., D.L.S.), University of Iowa Carver College of Medicine, Iowa City, Iowa 52242; and University Departments of Medicine and Clinical Research (G.S.H.Y., S.O.), Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge, CB22XY United Kingdom

Address all correspondence and requests for reprints to: Patricia A. Donohoue, M.D., Division of Endocrinology, Department of Pediatrics, The University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, Iowa 52242-1083. E-mail: patricia-donohoue{at}uiowa.edu.

Genetic and pharmacological studies have shown that the melanocortin-4 receptor (MC4R) is an important regulator of food intake and energy homeostasis. Consistent with these studies, several mutations of the MC4R gene have been identified as being associated with early-onset severe obesity. We report here the first in-frame deletion mutation of the MC4R gene (88–92) in an obese female patient with onset of obesity at less than 5 yr of age. Functional analysis revealed that the mutant receptor is expressed well on the cell surface but completely devoid of ligand binding and cAMP generation in response to agonist stimulation. We conclude that this novel mutation is the cause of obesity of this patient.

P.A.D. and Y.-X.T. made equal contributions to this study and should be considered as co-first authors.

This work was supported by National Institutes of Health Grant HD29569 (to P.A.D.), a Beginning-Grant-in-Aid (0265236Z) from the American Heart Association Heartland Affiliate (to Y.-X.T.), NIH Grant HD22196 (to D.L.S.), and a Pilot and Feasibility grant (to Y.-X.T.) from the Diabetes and Endocrinology Research Center of the University of Iowa (DK25295).

Abbreviations: BMI, Body mass index; HEK, human embryonic kidney; MC4R, melanocortin-4 receptor; -MSH, -melanocyte stimulating hormone; NDP-MSH, [Nle⁴, D-Phe⁷]--MSH; SSCP, single-strand conformational polymorphism; Wa/BSA, Waymouth’s MB752/1 containing BSA; wt, wild-type.

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