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, Valerie
AU - Casado, Pedro
AU - Blackburn, James
AU - Abollo-Jimenez, Fernando
AU - Marinelli, Eugenia
AU - Besser, Rachael E J
AU - Högler, Wolfgang
AU - Temple, I Karen
AU - Davies, Justin
AU - Gagunashvili, Andrey
AU - Robinson, Iain C A F
AU - Camper, Sally
AU - Davis, Shannon W
AU - Cutillas, Pedro R
AU - Gevers, Evelien F
AU - Aoki, Yoko
AU - Dattani, Mehul T
AU - Gaston-Massuet, Carles
PY - 2021
Y1 - 2021
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.
UR - https://pubmed.ncbi.nlm.nih.gov/33795686/
U2 - 10.1038/s41467-021-21712-4
DO - 10.1038/s41467-021-21712-4
M3 - Article
SN - 2041-1723
JO - nature communications
JF - nature communications
M1 - 2028
ER -
