Downregulation of the GHRH/GH/IGF1 axis in a mouse model of Börjeson-Forssman-Lehman syndrome

Development. 2020 Oct 23;147(21):dev187021. doi: 10.1242/dev.187021.

Abstract

Börjeson-Forssman-Lehmann syndrome (BFLS) is an intellectual disability and endocrine disorder caused by plant homeodomain finger 6 (PHF6) mutations. Individuals with BFLS present with short stature. We report a mouse model of BFLS, in which deletion of Phf6 causes a proportional reduction in body size compared with 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 (IGF1) in the liver. Phf6 deletion specifically in the nervous system caused a proportional growth defect, indicating a 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/IGF1 axis.

Keywords: BFLS; Börjeson-Forssman-Lehman Syndrome; Failure to thrive; Growth hormone; Growth hormone releasing hormone; IGF-1; Insulin-like growth factor 1; PHF6; Plant homeodomain finger protein 6; SOCS2; Suppressor of cytokine signaling 2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Disease Models, Animal
  • Down-Regulation*
  • Epilepsy / blood
  • Epilepsy / metabolism*
  • Epilepsy / pathology
  • Face / abnormalities*
  • Face / pathology
  • Fingers / abnormalities*
  • Fingers / pathology
  • Growth Disorders / blood
  • Growth Disorders / metabolism*
  • Growth Disorders / pathology
  • Growth Hormone / blood
  • Growth Hormone / metabolism*
  • Growth Hormone-Releasing Hormone / metabolism*
  • Hypogonadism / blood
  • Hypogonadism / metabolism*
  • Hypogonadism / pathology
  • Hypothalamus / metabolism
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism*
  • Male
  • Mental Retardation, X-Linked / blood
  • Mental Retardation, X-Linked / metabolism*
  • Mental Retardation, X-Linked / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nervous System / metabolism
  • Obesity / blood
  • Obesity / metabolism*
  • Obesity / pathology
  • Organ Specificity
  • Pituitary Gland / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Repressor Proteins / metabolism*
  • Signal Transduction*
  • Suppressor of Cytokine Signaling Proteins / metabolism

Substances

  • Phf6 protein, mouse
  • RNA, Messenger
  • Repressor Proteins
  • Socs2 protein, mouse
  • Suppressor of Cytokine Signaling Proteins
  • Insulin-Like Growth Factor I
  • Growth Hormone
  • Growth Hormone-Releasing Hormone

Supplementary concepts

  • Borjeson-Forssman-Lehmann syndrome