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Activating mutations in BRAF disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mice and humans

Activating mutations in BRAF disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mice and humans
Activating mutations in BRAF disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mice and humans
Germline mutations in BRAF and other components of the MAPK pathway are associated with the congenital syndromes collectively known as RASopathies. Here, we report the association of Septo-Optic Dysplasia (SOD) including hypopituitarism and Cardio-Facio-Cutaneous (CFC) syndrome in patients harbouring mutations in BRAF. Phosphoproteomic analyses demonstrate that these genetic variants are gain-of-function mutations leading to activation of the MAPK pathway. Activation of the MAPK pathway by conditional expression of the BrafV600E/+ allele, or the knock-in BrafQ241R/+ allele (corresponding to the most frequent human CFC-causing mutation, BRAF p.Q257R), leads to abnormal cell lineage determination and terminal differentiation of hormone-producing cells, causing hypopituitarism. Expression of the BrafV600E/+ allele in embryonic pituitary progenitors leads to an increased expression of cell cycle inhibitors, cell growth arrest and apoptosis, but not tumour formation. Our findings show a critical role of BRAF in hypothalamo-pituitary-axis development both in mouse and human and implicate mutations found in RASopathies as a cause of endocrine deficiencies in humans.
2041-1723
Gualtieri, Angelica
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Gregory, Louise C
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Vignola, Maria Lillina
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Nicholson, James G
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Inoue, Shin-Ichi
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Scagliotti, Valeria
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Casado, Pedro
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Blackburn, James
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Abollo-Jimenez, Fernando
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Besser, Rachael
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Temple, Karen
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Cutillas, Pedro
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Dattani, Mehul T.
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Gaston-Massuet, Carles
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Gualtieri, Angelica
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Gregory, Louise C
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Vignola, Maria Lillina
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Nicholson, James G
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Tan, Rachael
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Scagliotti, Valeria
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Casado, Pedro
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Blackburn, James
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Abollo-Jimenez, Fernando
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Temple, Karen
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Davies, Justin
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Gagunashvili, Andrey
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Robinson, Iain C.A.F.
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Davis, Shannon W
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Cutillas, Pedro
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Gevers, Evelien F
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Aoki, Yoko
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Dattani, Mehul T.
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Gaston-Massuet, Carles
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Gualtieri, Angelica, Kyprianou, Nikolina, Gregory, Louise C, Vignola, Maria Lillina, Nicholson, James G, Tan, Rachael, Inoue, Shin-Ichi, Scagliotti, Valeria, Casado, Pedro, Blackburn, James, Abollo-Jimenez, Fernando, Marinelli, Eugenia, Besser, Rachael, Hogler, Wolfgang, Temple, Karen, Davies, Justin, Gagunashvili, Andrey, Robinson, Iain C.A.F., Camper, Sally A, Davis, Shannon W, Cutillas, Pedro, Gevers, Evelien F, Aoki, Yoko, Dattani, Mehul T. and Gaston-Massuet, Carles (2021) Activating mutations in BRAF disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mice and humans. Nature Communications, 12 (1), [2028]. (doi:10.1038/s41467-021-21712-4).

Record type: Article

Abstract

Germline mutations in BRAF and other components of the MAPK pathway are associated with the congenital syndromes collectively known as RASopathies. Here, we report the association of Septo-Optic Dysplasia (SOD) including hypopituitarism and Cardio-Facio-Cutaneous (CFC) syndrome in patients harbouring mutations in BRAF. Phosphoproteomic analyses demonstrate that these genetic variants are gain-of-function mutations leading to activation of the MAPK pathway. Activation of the MAPK pathway by conditional expression of the BrafV600E/+ allele, or the knock-in BrafQ241R/+ allele (corresponding to the most frequent human CFC-causing mutation, BRAF p.Q257R), leads to abnormal cell lineage determination and terminal differentiation of hormone-producing cells, causing hypopituitarism. Expression of the BrafV600E/+ allele in embryonic pituitary progenitors leads to an increased expression of cell cycle inhibitors, cell growth arrest and apoptosis, but not tumour formation. Our findings show a critical role of BRAF in hypothalamo-pituitary-axis development both in mouse and human and implicate mutations found in RASopathies as a cause of endocrine deficiencies in humans.

Text
Angelica Gualtieri et al BRAF mutations disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mouse and humans Nature Communications 20201 - Accepted Manuscript
Available under License Creative Commons Attribution.
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Accepted/In Press date: 22 February 2021
Published date: 1 April 2021

Identifiers

Local EPrints ID: 448314
URI: http://eprints.soton.ac.uk/id/eprint/448314
ISSN: 2041-1723
PURE UUID: 34b9527b-9ecc-4e7b-8e2f-4638a34d9229
ORCID for Karen Temple: ORCID iD orcid.org/0000-0002-6045-1781

Catalogue record

Date deposited: 20 Apr 2021 16:30
Last modified: 18 Jun 2021 01:35

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Contributors

Author: Angelica Gualtieri
Author: Nikolina Kyprianou
Author: Louise C Gregory
Author: Maria Lillina Vignola
Author: James G Nicholson
Author: Rachael Tan
Author: Shin-Ichi Inoue
Author: Valeria Scagliotti
Author: Pedro Casado
Author: James Blackburn
Author: Fernando Abollo-Jimenez
Author: Eugenia Marinelli
Author: Rachael Besser
Author: Wolfgang Hogler
Author: Karen Temple ORCID iD
Author: Justin Davies
Author: Andrey Gagunashvili
Author: Iain C.A.F. Robinson
Author: Sally A Camper
Author: Shannon W Davis
Author: Pedro Cutillas
Author: Evelien F Gevers
Author: Yoko Aoki
Author: Mehul T. Dattani
Author: Carles Gaston-Massuet

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