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Skeletal muscle pathology in Costello and cardio-facio-cutaneous syndromes: Developmental consequences of germline Ras/MAPK activation on myogenesis


  • William E. Tidyman,

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    • William E. Tidyman, Ph.D., M.S. is an Associate Specialist in the Department of Orofacial Science at the University of California at San Francisco with extensive research experience in the study of both cardiac and skeletal muscle gene regulation and development. He was a member of the team that identified the genes responsible for CFC. His current research includes how Ras/MAPK signaling regulates skeletal myogenesis and how germline dysregulation of this pathway affects muscle development and causes pathology.

  • Han S. Lee,

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    • Han S. Lee, M.D., Ph.D. is an Assistant Professor in the Department of Anatomic Pathology, Division of Neuropathology at UCSF. His area of specialty includes surgical neuropathology and skeletal muscle pathology, with research interests including the study of drug-related toxicity in skeletal muscle.

  • Katherine A. Rauen MD, PhD

    Corresponding author
    • UCSF Helen Diller Family Comprehensive Cancer Center, 2340 Sutter Street, Room S429, PO Box 0808, San Francisco, CA 94115.
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    • Katherine A. Rauen, M.D., Ph.D. is an Associate Professor in the Departments of Pediatrics, Division of Medical Genetics and Obstetrics, Gynecology and Reproductive Sciences. Her clinical and basic science research focuses on the RASopathies in an effort to understand genetic mechanisms affecting common developmental and cancer pathways. She identified the genetic cause of CFC syndrome and started the first NF/Ras Pathway (RASopathy) Genetics Clinic at UCSF which is now emulated around the world.

  • How to Cite this Article: Tidyman WE, Lee HS, Rauen KA. 2011. Skeletal muscle pathology in Costello and cardio-facio-cutaneous syndromes: Developmental consequences of germline Ras/MAPK activation on myogenesis. Am J Med Genet Part C Semin Med Genet 157:104–114.


Cardio-facio-cutaneous syndrome (CFC) and Costello syndrome (CS) are two of the more rare RASopathies caused by altered signal transduction of the Ras/mitogen-activated protein kinase (MAPK) pathway. All of the RASopathies exhibit some degree of hypotonia, but CS and CFC are more severe. To determine if individuals with CS and CFC have an underlying skeletal myopathy, we systematically evaluated skeletal muscle pathology in both conditions. We reviewed pathology reports from six individuals who had undergone a skeletal muscle biopsy, and we reviewed histology slides on two cases with CS and one case with CFC. All patients in the cohort had histopathologic findings, and two consistent abnormalities were identified. The first was the presence of abnormal muscle fiber size and variability, and the second was the presence of type 2 fiber predominance. Given the degree of hypotonia typically present in these patients, the overall architecture of the muscle was relatively normal, without showing indications of severe structural histopathology or metabolic abnormalities. Because the Ras/MAPK pathway is vital for skeletal myogenesis, we evaluated the effects of CS and CFC mutations on myogenesis using C2C12 myoblasts. All CS/CFC mutations inhibited myoblast differentiation as indicated by fewer myosin heavy chain expressing cells and a decrease in the number of myotubes as compared to controls. These findings indicate that CS and CFC may have a true myopathy related to an inherent dysregulation of skeletal myogenesis, which further expands our understanding of the consequences of germline Ras/MAPK mutations. © 2011 Wiley-Liss, Inc.