Background Melanocortin 4 receptor (MC4R) deficiency is thecommonest monogenic form of obesity. However, the clinical spectrumand mode of inheritance have not been defined, pathophysiologicalmechanisms leading to obesity are poorly understood, and thereis little information regarding genotype–phenotype correlations.
Methods We determined the nucleotide sequence of the MC4R genein 500 probands with severe childhood obesity. Family studieswere undertaken to examine cosegregation of identified mutationswith obesity. Subjects with MC4R deficiency underwent metabolicand endocrine evaluation; the results were correlated with thesignaling properties of mutant receptors.
Results Twenty-nine probands (5.8 percent) had mutations inMC4R; 23 were heterozygous, and 6 were homozygous. Mutationcarriers had severe obesity, increased lean mass, increasedlinear growth, hyperphagia, and severe hyperinsulinemia; homozygoteswere more severely affected than heterozygotes. Subjects withmutations retaining residual signaling capacity had a less severephenotype.
Conclusions Mutations in MC4R result in a distinct obesity syndromethat is inherited in a codominant manner. Mutations leadingto complete loss of function are associated with a more severephenotype. The correlation between the signaling propertiesof these mutant receptors and energy intake emphasizes the keyrole of this receptor in the control of eating behavior in humans.
Source Information
From the Genetics of Obesity Collaborative Group (T.C.) and the University Departments of Medicine and Clinical Biochemistry (I.S.F., J.M.K., G.H.S.Y., E.J.L., S.O.'R.), Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, United Kingdom.
Address reprint requests to Dr. O'Rahilly at the Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom, or at sorahill{at}hgmp.mrc.ac.uk.
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