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Ras/ MAPK dysregulation in development causes a skeletal myopathy in an activating Braf L597V mouse model for cardio‐facio‐cutaneous syndrome
Author(s) -
Maeda Yoshiko,
Tidyman William E.,
Ander Bradley P.,
Pritchard Catrin A.,
Rauen Katherine A.
Publication year - 2021
Publication title -
developmental dynamics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.634
H-Index - 141
eISSN - 1097-0177
pISSN - 1058-8388
DOI - 10.1002/dvdy.309
Subject(s) - myogenesis , skeletal muscle , biology , mapk/erk pathway , costello syndrome , phenotype , myopathy , endocrinology , medicine , myocyte , protein kinase a , congenital myopathy , kinase , genetics , mutation , gene , muscle biopsy , biopsy , kras
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.