TY - JOUR
T1 - Activating mutations in BRAF disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mice and humans
AU - Gualtieri, Angelica
AU - Kyprianou, Nikolina
AU - Gregory, Louise C.
AU - Vignola, Maria Lillina
AU - Nicholson, James G.
AU - Tan, Rachael
AU - Inoue, Shin ichi
AU - Scagliotti, Valeria
AU - Casado, Pedro
AU - Blackburn, James
AU - Abollo-Jimenez, Fernando
AU - Marinelli, Eugenia
AU - Besser, Rachael E.J.
AU - Högler, Wolfgang
AU - Karen Temple, I.
AU - Davies, Justin H.
AU - Gagunashvili, Andrey
AU - Robinson, Iain C.A.F.
AU - Camper, Sally A.
AU - Davis, Shannon W.
AU - Cutillas, Pedro R.
AU - Gevers, Evelien F.
AU - Aoki, Yoko
AU - Dattani, Mehul T.
AU - Gaston-Massuet, Carles
N1 - Funding Information:
We apologise to the authors whose work we were unable to reference due to space constraints. We thank Simon Rhodes and J. Drouin for providing the PIT1 and TPIT antibodies. The human embryonic and foetal material was provided by the Joint MRC/ Wellcome Trust (grant# MR/R006237/1) Human Developmental Biology Resource (www. hdbr.org). The research is funded by Action Medical Research (GN 2272) and BTLC (GN 417/2238 and MGU0551). R.T. and J.B. were funded by MRC-CRTF (MR/P018459/1 and MR/S037896). V.S., M.L.V, A.G. and C.G.-M. were funded by Early Career Fellowship from the Medical College of Saint Bartholomew’s Hospital Trust. P.R.C. and P.C. were supported by grants from CRUK (C15966/A24375), BTLC (297/2249) and BBSRC (BB/ M006174/1). R.E.J.B. was funded by NIHR from an academic Clinical Lectureship award. Y.A. was supported by Japan Agency for Medical Research and Development under Grant (JP18ek0109241 and JP20ek0109470), and S.I. by JSPS KAKENHI Grant Number 18K07811. M.T.D. was funded by the Great Ormond Street Hospital (GOSH) Children’s Charity, the NIHR GOSH BRC, and partially funded by the Medical Research Foundation (MRF-099-0002-RG-UCLIC). The analysis performed by GOSgene in this study is in part supported by the National Institute for Health Research (NIHR), GOSH and the Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-21712-4
DO - 10.1038/s41467-021-21712-4
M3 - Article
C2 - 33795686
AN - SCOPUS:85103805974
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2028
ER -