Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-021-21712-4
Keywords
-
Categories
Funding
- Joint MRC/Wellcome Trust [MR/R006237/1]
- Action Medical Research [GN 2272]
- BTLC [GN 417/2238, MGU0551, 297/2249]
- MRC-CRTF [MR/P018459/1, MR/S037896]
- Medical College of Saint Bartholomew's Hospital Trust
- CRUK [C15966/A24375]
- BBSRC [BB/M006174/1]
- NIHR from an academic Clinical Lectureship award
- Japan Agency for Medical Research and Development [JP18ek0109241, JP20ek0109470]
- JSPS KAKENHI [18K07811]
- Great Ormond Street Hospital (GOSH) Children's Charity
- NIHR GOSH BRC
- Medical Research Foundation [MRF-099-0002-RG-UCLIC]
- National Institute for Health Research (NIHR)
- GOSH
- Biomedical Research Centre (BRC)
- MRC [MR/P018459/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/M006174/1] Funding Source: researchfish
- Medical Research Foundation [MRF-099-0002-RG-UCLIC] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [18K07811] Funding Source: KAKEN
Ask authors/readers for more resources
Mutations in BRAF and other components of the MAP kinase pathway are associated with RASopathies, leading to congenital syndromes such as Septo-Optic Dysplasia and Cardio-Facio-Cutaneous syndrome. The gain-of-function mutations in BRAF are shown to play a critical role in the development of the hypothalamo-pituitary axis, resulting in endocrine deficiencies in patients with RASopathies.
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 hormone-producing cells, causing hypopituitarism. Expression of the Braf(V600E/+) 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. Mutations in components of the MAP kinase pathway are associated with a group of syndromes known as RASopathies. Here, the authors identify gain-of-function mutations in BRAF in patients with RASopathies and congenital hypopituitarisms. This article demonstrates a central role for BRAF in the development of the hypothalamo-pituitary axis leading to endocrine deficiencies in patients with RASopathies.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available