ESPE Yearbook of Paediatric Endocrinology

Nat Med, 2021 Jun;27(6):1088–1096. 10.1038/s41591-021-01349-y. https://pubmed.ncbi.nlm.nih.gov/34045736/

This paper reports the high prevalence of MC4R loss-of-function (LoF) variants in a normal population and their large impact on longitudinally assessed anthropometric traits from birth to young adult life.

This is the first study to examine the prevalence of all non-synonymous MC4R variants in a large sample (5724 persons) of a representative birth cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC). ALSPAC examined over 75% of all children born in the larger Bristol area between 1990-1992, thus these data provide an accurate estimate of true prevalence in a (mainly white) European population.

Obesity is one of the most important non-communicable diseases and has finally now been acknowledged by EU commission as a disease in its own right (1). In contrast to polygenic obesity, monogenic obesity is much rarer. However, the prevalence reported here, 1 in 337, means that LoF MC4R variants can no longer be termed a rare disease.

The longitudinal characterization of participants in ALSPAC (2), provides a unique possibility to compare the development of anthropometric traits between MC4R LoF variant carriers (n=17) to non-LoF variant carriers (n=5707). They identify a large and stable influence of LoF MC4R variants on BMI, weight and body fat from 5 years onwards. Interestingly, in contrast to previous studies by the same authors (3, 4), no evidence for reduced systolic blood pressure or increased adult height was found after adjusting for age, sex and BMI.

Rare, non-synonymous wild-type like variant carriers (n=21) did not differ from wildtype or synonymous, common variant carriers. However, there is no individual analysis for wild-type like carriers offered and LoF was primarily defined as reduced cAMP generation upon MC4R stimulation in a heterologous cell system expressing the MC4R variant, although other MC4R signalling pathways have been described (5, 6). As for some of the here listed wild-type like variants, debates exist on their possible pathogenetic effects. A more detailed analysis would have been welcomed.

In conclusion, LoF MC4R variants conferring a reproducible risk for increased adiposity seem to be more frequent than previously assumed; hence a generous screening approach should be advocated, especially since some variants seem to be rescuable by synthetic MC4R activators, such as Setmelanotide (7).

References: 1. Burki T. European Commission classifies obesity as a chronic disease. Lancet Diabetes Endocrinol. 2021;9(7):418.2. Boyd A, Golding J, Macleod J, et al. Cohort Profile: the 'children of the 90s’–the index offspring of the Avon Longitudinal Study of Parents and Children. Int J Epidemiol. 2013;42(1):111–27.3. Greenfield JR, Miller JW, Keogh JM, Henning E, Satterwhite JH, Cameron GS, et al. Modulation of blood pressure by central melanocortinergic pathways. N Engl J Med. 2009;360(1):44–52.4. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003;348(12):1085–95.5. Sharma S, Garfield AS, Shah B, et al. Current Mechanistic and Pharmacodynamic Understanding of Melanocortin-4 Receptor Activation. Molecules. 2019;24(10).6. Brouwers B, de Oliveira EM, Marti-Solano M, et al. Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation. J. Cell Rep. 2021 Mar 23;34(12):108862. doi: 10.1016/j.celrep.2021.108862.7. Collet TH, Dubern B, Mokrosinski J, et al. Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency. Mol Metab. 2017;6(10):1321-9.