Ras/MAPK dysregulation in development causes a skeletal myopathy in an activating BrafL597V mouse model for cardio-facio-cutaneous syndrome

Background Cardio-facio-cutaneous (CFC) syndrome is a human multiple congenital anomaly syndrome that is caused by activating heterozygous mutations in either BRAF, MEK1, or MEK2, three protein kinases of the Ras/mitogen-activated protein kinase (MAPK) pathway. CFC belongs to a group of syndromes known as RASopathies. Skeletal muscle hypotonia is a ubiquitous phenotype of RASopathies, especially in CFC syndrome. To better understand the underlying mechanisms for the skeletal myopathy in CFC, a mouse model with an activating Braf(L597V) allele was utilized. Results The activating Braf(L597V) allele resulted in phenotypic alterations in skeletal muscle characterized by a reduction in fiber size which leads to a reduction in muscle size which are functionally weaker. MAPK pathway activation caused inhibition of myofiber differentiation during embryonic myogenesis and global transcriptional dysregulation of developmental pathways. Inhibition in differentiation can be rescued by MEK inhibition. Conclusions A skeletal myopathy was identified in the CFC Braf(L597V) mouse validating the use of models to study the effect of Ras/MAPK dysregulation on skeletal myogenesis. RASopathies present a novel opportunity to identify new paradigms of myogenesis and further our understanding of Ras in development. Rescue of the phenotype by inhibitors may help advance the development of therapeutic options for RASopathy patients.

Automated summary

Cardio-facio-cutaneous (CFC) syndrome is a congenital anomaly syndrome caused by activating mutations in BRAF, MEK1, or MEK2 kinases. A mouse model with an activating Braf(L597V) allele was used to study skeletal muscle myopathy in CFC, revealing phenotypic alterations and global transcriptional dysregulation. Inhibition of myofiber differentiation can be rescued by MEK inhibition, suggesting therapeutic potential for RASopathy patients.