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

Nat Commun. 2021 Apr 1;12(1):2028. doi: 10.1038/s41467-021-21712-4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Corticotrophs / cytology
  • Corticotrophs / 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
  • Melanotrophs / metabolism
  • Mice, Knockout
  • Mice, Transgenic
  • Pituitary Gland / metabolism*
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins B-raf / metabolism
  • Whole Exome Sequencing / methods


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

Supplementary concepts

  • Cardiofaciocutaneous syndrome