ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Clin Endocrinol Metab. 2018 Feb 1;103(2):649-659

A minimum level of energy availability is required for the onset of puberty, whereas increased fat mass has been shown to be associated with precocious onset of puberty^1,2. Recent genome-wide association studies have identified several loci for age at menarche also associated with obesity^3-5. Whether such genes may regulate pubertal timing exclusively via impact on fat mass or via other body mass index (BMI)–independent mechanisms is unknown. Here, Howard et al. performed whole-exome sequencing in 67 families with delayed puberty and 35 controls. They identified potentially pathogenic, rare variants in genes in linkage disequilibrium with genome-wide association studies of age at menarche loci in 283 genes. Of these, five genes were implicated in the control of body mass. After filtering for segregation with trait, only one candidate gene, fat mass and obesity-associated gene (FTO), was retained. FTO has been previously described in the literature as involved in pathways of energy homeostasis and growth. It was the first obesity-susceptibility gene identified through genome wide association studies and continues to be the locus with the largest effect on BMI and obesity risk. FTO has been identified as an amino acid sensor acting, via mTOR, to influence appropriate levels of development and translation⁶. It is expressed within the hypothalamus in several sites critical for energy balance, including in the arcuate nucleus within pro-opiomelanocortin neurons⁷. In silico analysis indicated that the patients’ mutations may have a subtle effect in protein–protein interaction and lead to a change in FTO activity in vivo. Those patients with delayed puberty identified with FTO variants showed reductions in body mass. The FTO variants carried by the DP patients may result in reduced fat mass, which would in turn contribute to a delay in the timing of pubertal onset. FTO deficiency in vivo results in delayed puberty marked by vaginal opening in mice. Notably, body weight was not significantly different between the two pup genotype groups. In summary, those results have identified variants in FTO as a potential contributory factor in the development of self-limited delayed puberty.

1. Kaplowitz PB, Slora EJ, Wasserman RC, Pedlow SE, Herman-Giddens ME. Earlier onset of puberty in girls: relation to increased body mass index and race. Pediatrics. 2001;108(2):347–353.

2. He Q, Karlberg J. BMI in childhood and its association with height gain, timing of puberty, and final height. Pediatr Res. 2001;49(2): 244–251.

3. C.E. Elks, J.R. Perry, P. Sulem, D.I. Chasman, N. Franceschini, C. He, K.L., et al. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies. Nat Genet 2010; 42: 1077-85.

4. M. den Hoed, U. Ekelund, S. Brage, A. Grontved, J.H. Zhao, S.J. Sharp, K.K. Ong, N.J. Wareham, and R.J. Loos, Genetic susceptibility to obesity and related traits in childhood and adolescence: influence of loci identified by genome-wide association studies. Diabetes 2010; 59: 2980-8.

5. L. Fernandez-Rhodes, E.W. Demerath, D.L. Cousminer, R. Tao, J.G. Dreyfus, T. Esko, et al. Association of adiposity genetic variants with menarche timing in 92,105 women of European descent. Am J Epidemiol 2013; 178: 451-60.

6. Speakman JR. The “fat mass and obesity related” (FTO) gene: mechanisms of impact on obesity and energy balance. Curr Obes Rep. 2015;4(1):73–91.

7. Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, Hewitson KS, Yeo GS, McDonough MA, Cunliffe S, McNeill LA, Galvanovskis J, Rorsman P, Robins P, Prieur X, Coll AP, Ma M, Jovanovic Z, Farooqi IS, Sedgwick B, Barroso I, Lindahl T, Ponting CP, Ashcroft FM, O’Rahilly S, Schofield CJ. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science. 2007;318(5855):1469–1472.