SAT-203 Methylation Status of Growth Hormone Receptor (GHR), Insulin-like Growth Factor 1 Receptor (IGF1R) and Insulin Receptor (INSR) in Small for Gestational Age (SGA) Boys without Catch-up Growth

Abstract Disclosure: L. Zoff: None. F.M. Garcia: None. G. Veneruzzo: None. G. Aschettino: None. M. Valdora: None. D. Rodriguez: None. M.C. Mattone: None. N. Perez Garrido: None. R.M. Marino: None. C. Alonso: None. G. Guercio: None. A. Belgorosky: None. M.S. Baquedano: None. About 11% of all children born annually in the world are defined as SGA. Approximately 15% of them will continue to present with low height for their ages, associated with a non-catch-up growth phenotype. However, the pathophysiological mechanism underlying these findings is unknown. Several studies have suggested that the embryonic environmental characteristics of patients SGA could induce changes at the epigenetic level that affect gene transcription and would be stable throughout life. The GH/IGF1 axis and insulin are crucial stimulators of growth, cell proliferation, and metabolism. This study aimed to compare the methylation status of GHR, IGF1R, and INSR genes in peripheral blood in a cohort of boys with idiopathic short stature without GH-treatment who were born SGA (birthweight <10th percentile for the gestation, n=14; 4-13yr) and in age-matched control boys (CTRL, n=19; 4-15yr)using targeted deep-amplicon bisulfite sequencing on a MiSeq system. Sequencing libraries of 4 promoter CpG-rich regions for GHR, 3 for IGF1R and 5 for INSR (104, 103 and 141 CpG sites, respectively) were analyzed for mean methylation values of all CpG sites using amplikyzer2 software. The PCA score plot showed a clear separation between the CTRL and SGA groups. The two principal components explained 92.5% of the variance. The mean CpG methylation levels of the SP1-responsive IGF1R proximal promoter [GRCh38:15:98648387: 98648592:1 (-152 to +53)] were significantly higher in SGA than in CTRL (Mann-Whitney-Wilcoxon test, p<0.05). Compared with CNTRL, the CpG methylation levels of the TATA-less V2 proximal promoter as well as within the V2, V3, and V9 alternative exons in the regulatory 5´-UTR of the GHR gene [GRCh38:5:42423379:42423768:1 (-59 to +330), GRCh38:5:42424357:42424668:1 (+919 a +1230) and GRCh38:5:42424672:42424968:1 (+1234 a +1530)] were lower in SGA (p<0.05). Promoter DNA methylation is a fundamental epigenetic mark associated with transcriptional repression during development. According to our findings, it could be speculated that epigenetic repression of IGF1R might contribute to the lack of catch-up growth in short SGA patients. Finally, the human GHR gene is a complex transcription unit, and the impact or functional relevance of our findings and its relation to lessen activation of IGF1R pathways remains to be elusive. Presentation: Saturday, July 12, 2025