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. DavisPedro R. Cutillas, Evelien F. Gevers, Yoko Aoki, Mehul T. Dattani, Carles Gaston-Massuet

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


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.

Original languageEnglish
Article number2028
JournalNature Communications
Issue number1
Publication statusPublished - 2021 Dec 1


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