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

Angelica Gualtieri, Nikolina Kyprianou, Louise C. Gregory, Maria Lillina Vignola, James G. Nicholson, Rachael Tan, Shin-ichi Inoue, Valeria Scagliotti, Pedro Casado, James Blackburn, Fernando Abollo-Jimenez, Eugenia Marinelli, Rachael E. J. Besser, Wolfgang Högler, I. Karen Temple, Justin H. Davies, Andrey Gagunashvili, Iain C.A.F. Robinson, Sally A. Camper, Shannon W. Davis, Pedro R. Cutillas, Evelien F. Gevers, Yoko Aoki, Mehul T. Dattani and Carles Gaston-Massuet ()
Additional contact information
Angelica Gualtieri: Queen Mary University of London
Nikolina Kyprianou: Queen Mary University of London
Louise C. Gregory: Great Ormond Street Institute of Child Health
Maria Lillina Vignola: Queen Mary University of London
James G. Nicholson: Queen Mary University of London
Rachael Tan: Queen Mary University of London
Shin-ichi Inoue: Tohoku University School of Medicine
Valeria Scagliotti: Queen Mary University of London
Pedro Casado: Queen Mary University of London
James Blackburn: Queen Mary University of London
Fernando Abollo-Jimenez: Queen Mary University of London
Eugenia Marinelli: Queen Mary University of London
Rachael E. J. Besser: Great Ormond Street Institute of Child Health
Wolfgang Högler: Johannes Kepler University Linz
I. Karen Temple: University of Southampton
Justin H. Davies: University of Southampton
Andrey Gagunashvili: Children NHS Foundation Trust and UCL
Iain C.A.F. Robinson: The Francis Crick Institute
Sally A. Camper: University of Michigan
Shannon W. Davis: University of South Carolina
Pedro R. Cutillas: Queen Mary University of London
Evelien F. Gevers: Queen Mary University of London
Yoko Aoki: Tohoku University School of Medicine
Mehul T. Dattani: Great Ormond Street Institute of Child Health
Carles Gaston-Massuet: Queen Mary University of London

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21712-4

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