ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This study examined the role of the melanocortin 3 receptor ( MC3R ) gene in regulating body weight, height, and puberty timing. It found an association between various non-synonymous variants (NSVs) in the MC3R gene with energy homeostasis and puberty.

Melanocortin 3 receptor (MC3R) is a G protein-coupled receptor involved in the hypothalamic system that regulates energy homeostasis, growth and puberty (1,2). Recent studies in MC3R -knockout mice showed an altered body weight regulation, severe insulin resistance and lipid profile alterations (3,4). In this study, Sanger sequencing of the coding region of MC3R was performed in 185 children or adolescents with short normal stature (SNS) or 258 individuals with severe obesity, and 192 healthy-lean individuals. 11 variants (6 NSVs) were identified. Notably, 3 rare loss-of-function (LoF) variants (p.Phe45Ser, p.Arg220Ser, and p.Ile298Ser) were exclusively found in severely obese individuals, suggesting a potential link between these variants and severe obesity. Conversely, the novel NSV p.Ala214Val, predicted to increase protein stability, was identified in a single lean female. In-silico analyses performed for all detected variants, suggested that four missense variants, including p.Ala214Val, may have pathogenic effects, with p.Ala214Val potentially increasing protein stability. The interaction network for MC3R, generated using GeneMANIA, identified 20 genes linked to BMI, height, and puberty timing.

In conclusion, the study underscores the importance of MC3R in body weight regulation, growth, and puberty timing. The identification of specific MC3R variants in obese individuals and in children with SNS suggests that variants in this gene may contribute to these conditions (5).

References: 1. Hinney A, Volckmar AL, Antel J. Genes and the hypothalamic control of metabolism in humans. Best Pract Res Clin Endocrinol Metab. 2014 Oct;28(5):635-47. doi: 10.1016/j.beem.2014.04.007. Epub 2014 Apr 26. PMID: 25256760\. 28, 635–647 (2014).2. Lam BYH, Williamson A, Finer S, Day FR, Tadross JA, Gonçalves Soares A, Wade K, Sweeney P, Bedenbaugh MN, Porter DT, Melvin A, Ellacott KLJ, Lippert RN, Buller S, Rosmaninho-Salgado J, Dowsett GKC, Ridley KE, Xu Z, Cimino I, Rimmington D, Rainbow K, Duckett K, Holmqvist S, Khan A, Dai X, Bochukova EG; Genes & Health Research Team; Trembath RC, Martin HC, Coll AP, Rowitch DH, Wareham NJ, van Heel DA, Timpson N, Simerly RB, Ong KK, Cone RD, Langenberg C, Perry JRB, Yeo GS, O’Rahilly S. MC3R links nutritional state to childhood growth and the timing of puberty. Nature. 2021 Nov;599(7885):436-441. doi: 10.1038/s41586-021-04088-9. Epub 2021 Nov 3. PMID: 34732894; PMCID: PMC8819628.3. Butler AA, Cone RD. Knockout studies defining different roles for melanocortin receptors in energy homeostasis. Ann N Y Acad Sci. 2003 Jun;994:240-5. doi: 10.1111/j.1749-6632.2003.tb03186.x. PMID: 12851322.4. You P, Hu H, Chen Y, Zhao Y, Yang Y, Wang T, Xing R, Shao Y, Zhang W, Li D, Chen H, Liu M. Effects of Melanocortin 3 and 4 Receptor Deficiency on Energy Homeostasis in Rats. Sci Rep. 2016 Oct 7;6:34938. doi: 10.1038/srep34938. PMID: 27713523; PMCID: PMC5054679.5. Renquist BJ, Lippert RN, Sebag JA, Ellacott KL, Cone RD. Physiological roles of the melanocortin MC3 receptor. Eur J Pharmacol. 2011 Jun 11;660(1):13-20. doi: 10.1016/j.ejphar.2010.12.025. Epub 2011 Jan 3. PMID: 21211527; PMCID: PMC3095771.