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

Helen M. McRae; Samantha Eccles; Lachlan Whitehead; Warren S. Alexander; Jozef Gécz; Tim Thomas; Anne K. Voss

doi:10.1242/dev.187021

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

Helen M. McRae, Samantha Eccles, Lachlan Whitehead, Warren S. Alexander, Jozef Gécz, Tim Thomas, Anne K. Voss

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

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.

Original language	English
Article number	dev187021
Journal	Development (Cambridge)
Volume	147
Issue number	21
DOIs	https://doi.org/10.1242/dev.187021
Publication status	Published or Issued - Nov 2020
Externally published	Yes

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

ASJC Scopus subject areas

Molecular Biology
Developmental Biology

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10.1242/dev.187021

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title = "Downregulation of the GHRH/GH/IGF1 axis in a mouse model of B{\"o}rjeson-Forssman-Lehman syndrome",

abstract = "B{\"o}rjeson-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.",

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author = "McRae, {Helen M.} and Samantha Eccles and Lachlan Whitehead and Alexander, {Warren S.} and Jozef G{\'e}cz and Tim Thomas and Voss, {Anne K.}",

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year = "2020",

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doi = "10.1242/dev.187021",

language = "English",

volume = "147",

journal = "Development (Cambridge)",

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AU - McRae, Helen M.

AU - Eccles, Samantha

AU - Whitehead, Lachlan

AU - Alexander, Warren S.

AU - Gécz, Jozef

AU - Thomas, Tim

AU - Voss, Anne K.

PY - 2020/11

Y1 - 2020/11

N2 - 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.

AB - 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.

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KW - Insulin-like growth factor 1

KW - PHF6

KW - Plant homeodomain finger protein 6

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KW - Suppressor of cytokine signaling 2

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

Abstract

Keywords

ASJC Scopus subject areas

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