Background: BRAF is a component of the RAS/MAPK signalling pathway; germline mutations in components of this pathway are associated with congenital abnormalities such as Cardio-Facio-Cutaneous (CFC), Noonan and Costello Syndromes. These syndromes, known as RASopathies, are characterised by variably penetrant central nervous system, cardiac and facial abnormalities. Importantly, short stature and delayed puberty have been associated with these syndromes, as have features of septo-optic dysplasia (SOD). Although a BRAF mutation, p.V600E, has been associated with papillary craniopharyngiomas, a direct causative role for this MAPK effector in hypothalamo-pituitary (HP) axis development has not been reported.
Objective and hypotheses: We hypothesised that BRAF is essential for the integrity of HP-axis development and that BRAF mutations are causative of congenital hypopituitarism. We aimed to understand the direct role of MAPK pathways in HP-axis development.
Methods: We expressed mutated BRAFV600E in a tissue-specific manner in the pituitary and hypothalamus in mice. By genetically targeting these tissues, we can identify the direct consequence of MAPK over-activation in HP-axis development. Additionally, BRAF was sequenced in patients with clinical features of CFC and congenital hypopituitarism/SOD.
Results: Tissue specific transgene activation of BRAFV600E/+ allele in murine HP-axis resulted in severe pituitary hyperplasia and failure of terminally differentiated cell-types leading to dwarfism. This phenotype indicates for the first time a direct and critical role for BRAF in HP-axis development leading to congenital hypopituitarism, which resembles the human phenotypes observed in association with BRAF mutations. Four genetic variants in BRAF were identified in the patients.
Conclusion: Our data, together with the functional characterisation of 4 novel genetic variants identified in unrelated children with CFC/congenital hypopituitarism/SOD, reveal a previously unreported role of BRAF in pituitary development leading to endocrine deficits. Our data link mutations in the MAPK pathway present in CFC and other RASopathies with HP-axis developmental abnormalities, leading to endocrinopathies.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology