ESPEYB19 7. Puberty Basic Science (7 abstracts)
7.12. MC3R links nutritional state to childhood growth and the timing of puberty
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 X , Genes & Health Research Team X , Martin X , Coll X , Rowitch X , Wareham X , van Heel X , Timpson X , Simerly X , Ong X , Cone X , Langenberg X , Perry X , Yeo X & O’Rahilly X
Nature. 2021 Nov;599(7885):436-441. doi: 10.1038/s41586-021-04088-9. Epub 2021 Nov 3. PMID: 34732894. https://www.nature.com/articles/s41586-021-04088-9
Brief Summary: This combination of a multi-cohort and animal studies describes the clinical impact of MC3R gene mutations. The authors identified a clinical syndrome caused by MC3R deficiency associating pubertal delay, short stature and low IGF1 levels, illustrating the role of MC3R in linking nutritional state to growth and puberty.
The melanocortin system controls food intake and energy expenditure, while its role in puberty is unknown [1]. MC3R encodes a receptor in the brain [2],[3] for which a role in growth and puberty has been hypothesized [4],[5]. This study characterizes the role of MC3R through the evaluation of functional impairment associated with naturally occurring mutations. 200,000 subjects of the UK Biobank study were analyzed by whole-exome-sequencing. MC3R loss-of-function mutations were associated with moderate pubertal delay, shorter stature and lower serum IGF1 levels, lower lean mass but no difference in BMI or body fat. Among 3 of the more common variants, 2 showed functional impairment evaluated by cAMP production after stimulation with α-MSH in vitro while one had normal function, but all were phenotypically associated with delayed puberty. Variants associated with in vitro loss-of-function (LoF) correlated with larger effects on puberty, height and lean mass. One subject with a rare homozygous LoF mutation had delayed puberty, normal fertility, markedly short stature, low sitting/standing height ratio, low IGF1 levels and severe obesity. Through RNA sequencing in mice, the authors found enriched MC3R expression in KNDy and GHRH neurons, and increasing expression during postnatal development. MC3R-deficient mice had delayed sexual maturation, demonstrating a conservation of MC3R function through species.
This study identified a new clinical syndrome caused by MC3R deficiency, characterized by delayed puberty, short stature and low IGF1 levels. Importantly, it strengthens the evidence for a link between pubertal timing and nutrtional status as observed in overweight or underweight children, and proposes a plausible causal association between greater caloric availability and the global trends towards taller human height and earlier onset of puberty, which have been documented for several decades.
References: 1. Cone RD. (2005) “Anatomy and regulation of the central melanocortin system.” Nat Neurosci.; 8(5):571–8. 2. Gantz I, Konda Y, Tashiro T, Shimoto Y, Miwa H, Munzert G, Watson SJ, DelValle J, Yamada T. (1993) “Molecular cloning of a novel melanocortin receptor. J Biol Chem.; 268(11):8246–50. 3. Roselli-Rehfuss L, Mountjoy KG, Robbins LS, Mortrud MT, Low MJ, Tatro JB, Entwistle ML, Simerly RB, Cone RD. (1993) “Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system.” Proc Natl Acad Sci U S A.; 90(19):8856–60. 4. Day FR et al. (2017) “Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk.” Nat Genet.; 49(6):834–841. 5. Wood AR et al., (2014) “Defining the role of common variation in the genomic and biological architecture of adult human height,” Nat Genet.; 46(11):1173–86.
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ESPE Yearbook of Paediatric Endocrinology
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