[HTML][HTML] Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene

IS Farooqi, JM Keogh, GSH Yeo, EJ Lank… - … England Journal of …, 2003 - Mass Medical Soc
New England Journal of Medicine, 2003Mass Medical Soc
Background Melanocortin 4 receptor (MC4R) deficiency is the commonest monogenic form
of obesity. However, the clinical spectrum and mode of inheritance have not been defined,
pathophysiological mechanisms leading to obesity are poorly understood, and there is little
information regarding genotype–phenotype correlations. Methods We determined the
nucleotide sequence of the MC4R gene in 500 probands with severe childhood obesity.
Family studies were undertaken to examine cosegregation of identified mutations with …
Background
Melanocortin 4 receptor (MC4R) deficiency is the commonest monogenic form of obesity. However, the clinical spectrum and mode of inheritance have not been defined, pathophysiological mechanisms leading to obesity are poorly understood, and there is little information regarding genotype–phenotype correlations.
Methods
We determined the nucleotide sequence of the MC4R gene in 500 probands with severe childhood obesity. Family studies were undertaken to examine cosegregation of identified mutations with obesity. Subjects with MC4R deficiency underwent metabolic and endocrine evaluation; the results were correlated with the signaling properties of mutant receptors.
Results
Twenty-nine probands (5.8 percent) had mutations in MC4R; 23 were heterozygous, and 6 were homozygous. Mutation carriers had severe obesity, increased lean mass, increased linear growth, hyperphagia, and severe hyperinsulinemia; homozygotes were more severely affected than heterozygotes. Subjects with mutations retaining residual signaling capacity had a less severe phenotype.
Conclusions
Mutations in MC4R result in a distinct obesity syndrome that is inherited in a codominant manner. Mutations leading to complete loss of function are associated with a more severe phenotype. The correlation between the signaling properties of these mutant receptors and energy intake emphasizes the key role of this receptor in the control of eating behavior in humans.
The New England Journal Of Medicine