Life Sciences Commons^™

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, Carles Gaston-Massuet

Faculty Publications

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 Braf^V600E/+ allele, or the knock-in Braf^Q241R/+ allele (corresponding to the most frequent human CFC-causing mutation, BRAF p.Q257R), leads to abnormal cell lineage determination and terminal differentiation of …