Downregulation of the GHRH/GH/IGF-1 axis in a mouse model of Börjeson-Forssman-Lehman Syndrome

The Börjeson–Forssman–Lehmann syndrome (BFLS) is an intellectual disability and endocrine disorder caused by plant homeodomain finger 6 (PHF6) mutations. BFLS patients present with short stature. We report a mouse model of BFLS, in which deletion of Phf6 causes a proportional reduction in body size compared to control mice. Growth hormone (GH) levels were reduced in the absence of PHF6. Phf6−/Y animals displayed a reduction in the expression of the genes encoding GH releasing hormone (GHRH) in the brain, GH in the pituitary gland and insulin-like growth factor-1 (IGF-1) in the liver. Phf6 deletion specifically in the nervous system caused a proportional growth defect, indicating neuroendocrine contribution to the phenotype. Loss of suppressor of cytokine signaling 2 (SOCS2), a negative regulator of growth hormone signaling partially rescued body size, supporting a reversible deficiency in GH signaling. These results demonstrate that PHF6 regulates the GHRH/GH/IGF-1 axis.