MON-052 - TMEM263 Modulates the GH/IGF-1 Axis to Control Growth and Metabolism

Genome-wide association studies (GWAS) have identified numerous candidate genes implicated in longitudinal bone growth and bone mass. One of these candidate genes, TMEM263, encodes a poorly characterized plasma membrane protein. Single nucleotide polymorphisms in TMEM263 are associated with bone mineral density in humans, and mutations are associated with dwarfism in chicken and severe skeletal dysplasia in at least one human fetus. Whether this genotype-phenotype relationship is causal, however, remains unclear. Our studies demonstrate that TMEM263 is required for postnatal growth through regulation of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis, a central endocrine pathway that integrates skeletal development with whole-body metabolism. Whole body deletion of Tmem263 in mice results in severe postnatal growth failure, proportional dwarfism, and impaired skeletal acquisition. While body weight is comparable to controls during the first two postnatal weeks, Tmem263-null mice exhibit a pronounced growth deficit postnatal day 21 onwards, coinciding with activation of GH/IGF-1 signaling. These mice display markedly reduced hepatic growth hormone receptor (GHR) expression, resulting in decreased circulating IGF-1 levels and impaired GH-induced JAK2/STAT5 signaling. This disruption leads to broad alterations in GH-regulated genes in the liver, reduced bone mass, and shortened growth plates. Collectively, our data establish a causal role for TMEM263 in postnatal growth via the GH–IGF-1 axis and raise the possibility that rare variants in TMEM263 contribute to combined skeletal and metabolic phenotypes. Given the central role of GH–IGF-1 signaling in regulating glucose, lipid, and protein metabolism, these findings suggest that TMEM263 may influence systemic metabolic homeostasis in addition to linear growth. Ongoing studies are actively investigating the metabolic consequences of TMEM263 deficiency, including effects on hepatic metabolism and whole-body energy balance.

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