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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 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.

SUBMITTER: Gualtieri A

PROVIDER: S-EPMC8016902 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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

Gualtieri Angelica A Kyprianou Nikolina N Gregory Louise C LC Vignola Maria Lillina ML Nicholson James G JG Tan Rachael R Inoue Shin-Ichi SI Scagliotti Valeria V Casado Pedro P Blackburn James J Abollo-Jimenez Fernando F Marinelli Eugenia E Besser Rachael E J REJ Högler Wolfgang W Karen Temple I I Davies Justin H JH Gagunashvili Andrey A Robinson Iain C A F ICAF Camper Sally A SA Davis Shannon W SW Cutillas Pedro R PR Gevers Evelien F EF Aoki Yoko Y Dattani Mehul T MT Gaston-Massuet Carles C

Nature communications 20210401 1

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 condi ...[more]

PMID: 33795686

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Dataset Information

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

Publications

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

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