journal contribution posted on 18.08.2021, 09:00 by Yoshiko Maeda, William E Tidyman, Bradley P Ander, Catrin A Pritchard, Katherine A Rauen
BackgroundCardio-facio-cutaneous syndrome (CFC) 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 BrafL597V allele was utilized.
ResultsThe activating BrafL597V allele resulted in phenotypic alterations in skeletal muscle characterized by a reduction in fiber size which lead 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.
ConclusionsA skeletal myopathy was identified in the CFC BrafL597V 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. This article is protected by copyright. All rights reserved.
National Cancer Institute
Comprehensive Cancer Center
University of California, Davis
UC Davis Genome Center
NIH/NIAMS. Grant Number: RO1AR062165
CitationDevelopmental dynamics, 250, 8, 2021, pp. 1074-1095
Author affiliationLeicester Cancer Research Centre, University of Leicester
VersionAM (Accepted Manuscript)
Published inDevelopmental dynamics
Spatial coverageUnited States