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

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 2028 (04 01 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 33795686 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• Proto-Oncogene Proteins B-raf

Topics

• Animals
• Cell Cycle Proteins (genetics, metabolism)
• Cells, Cultured
• Child
• Child, Preschool
• Corticotrophs (cytology, metabolism)
• Ectodermal Dysplasia (genetics)
• Facies
• Failure to Thrive (genetics)
• Gain of Function Mutation
• HEK293 Cells
• Heart Defects, Congenital (genetics)
• Humans
• Hypopituitarism (genetics)
• Hypothalamus (metabolism)
• Infant
• MAP Kinase Signaling System (genetics)
• Melanotrophs (cytology, metabolism)
• Mice, Knockout
• Mice, Transgenic
• Pituitary Gland (metabolism)
• Proto-Oncogene Proteins B-raf (genetics, metabolism)
• Exome Sequencing (methods)