Related Experiment Video

Updated: Nov 19, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

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Ras/MAPK dysregulation in development causes a skeletal myopathy in an activating BrafL597V mouse model for

Yoshiko Maeda1,2, William E Tidyman1,2, Bradley P Ander2,3

  • 1Department of Pediatrics, University of California Davis, Sacramento, California, USA.

Developmental Dynamics : an Official Publication of the American Association of Anatomists
|February 1, 2021
PubMed
Abstract

Insights

Cardio-facio-cutaneous syndrome, a RASopathy, causes muscle weakness due to BRAF mutations affecting myogenesis. Mouse models reveal skeletal myopathy, offering insights for potential therapeutic interventions.

Area of Science:

  • Molecular biology
  • Developmental biology
  • Genetics

Background:

  • Cardio-facio-cutaneous (CFC) syndrome is a human congenital anomaly caused by mutations in BRAF, MEK1, or MEK2, part of the Ras/mitogen-activated protein kinase (MAPK) pathway.
  • CFC syndrome is classified as a RASopathy, characterized by skeletal muscle hypotonia, particularly in affected individuals.
  • Understanding the mechanisms of skeletal myopathy in CFC syndrome is crucial, prompting the use of a Braf-mutant mouse model.

Purpose of the Study:

  • To investigate the mechanisms underlying skeletal myopathy in CFC syndrome.
  • To validate the use of a Braf-mutant mouse model for studying Ras/MAPK pathway effects on skeletal myogenesis.
  • To explore potential therapeutic strategies for RASopathies.

Main Methods:

  • Utilized a mouse model with an activating BrafL597V allele to study CFC syndrome.
  • Analyzed phenotypic alterations in skeletal muscle, including fiber size and muscle mass.
  • Investigated the impact of MAPK pathway activation on embryonic myogenesis and transcriptional regulation.

Main Results:

  • The BrafL597V allele induced skeletal muscle myopathy, characterized by reduced fiber size, decreased muscle size, and functional weakness.
  • MAPK pathway activation led to inhibited myofiber differentiation during embryonic development and dysregulated developmental gene expression.
  • The observed inhibition of differentiation was reversible with MEK inhibition.

Conclusions:

  • A skeletal myopathy was identified in the CFC BrafL597V mouse model, confirming its utility for studying Ras/MAPK dysregulation in myogenesis.
  • RASopathies offer new insights into myogenesis and the role of Ras in development.
  • Reversing the phenotype with MEK inhibitors suggests potential therapeutic avenues for RASopathy patients.
Keywords:
MEK inhibitorRASopathiesRas/MAPKhypotoniap38 MAPK

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