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A frameshift mutation in MC4R associated with dominantly inherited human obesity

Nature Genetics volume 20, pages 111–112 (1998)Cite this article

The melanocortin-4 receptor (MC4R) is a G-protein coupled, seven-transmembrane receptor which is highly expressed in the hypothalamus, a region of the brain intimately involved in appetite regulation1. It is a high-affinity receptor for αMSH, a product of the pro-opiomelanocortin (POMC) gene, which inhibits feeding when administered to rodents2. Hypothalamic POMC neurons are stimulated by leptin, an adipocyte-specific hormone which regulates appetite and energy expenditure, and constitute a link between leptin and the melanocortin system. Mc4r-deficient mice are hyperphagic, severely obese, hyperinsulinaemic and show increased linear growth3. Mice heterozygous for a null Mc4r allele exhibit weight gain intermediate to that seen in wild-type and homozygous mutant littermates. Additionally, ectopic expression in the brain of agouti4 and agouti-related transcript5, natural antagonists of the MC4R ligand, αMSH, results in obesity in rodents. In humans, obesity syndromes associated with abnormalities in POMC (ref. 6) and prohormone processing defects involving POMC ( ref. 7) have also been described.

The finding of a phenotype associated with a frameshift mutation in a G-protein coupled receptor gene is suggestive of haplo-insufficiency rather than dominant-negativity as, in general, members of this family of receptors function as monomers8. Although this family is insufficiently large to determine the statistical probability of the causal nature of this mutation, the fact that haplo-insufficiency for Mc4r in mice leads to obesity provides support for the notion that the MC4R mutation and the obesity of the two affected subjects are causally linked.

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Figure 1: A frameshift mutation in MC4R is associated with dominantly inherited obesity.
Figure 2: Auxology for subjects heterozygous for a frameshift mutation in MC4R.

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Acknowledgements

We thank G. Cook for her help in establishing the patient cohort and the many clinicians who have referred patients to us. S.O.R. & I.S.F are supported by the Wellcome Trust.

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Author notes

  1. Richard G. Stanhope: Institute of Child Health and Great Ormond Street Hospital , London, U.K. *G.S.H.Y. and I.S.F. contributed equally to this work.

Authors and Affiliations

  1. University Departments of Medicine and Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, UK

    Giles S.H. Yeo *, I. Sadaf Farooqi *, Shiva Aminian, David J. Halsall & Stephen O'Rahilly

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  1. Giles S.H. Yeo *
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Correspondence to Stephen O'Rahilly.

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Yeo, G., Farooqi, I., Aminian, S. et al. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 20, 111–112 (1998). https://doi.org/10.1038/2404

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