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Myopathy caused by HRAS germline mutations: implications for disturbed myogenic differentiation in the presence of constitutive HRas activation
  1. Ineke van der Burgt1,
  2. William Kupsky2,
  3. Stephani Stassou3,
  4. Ali Nadroo3,
  5. Cândida Barroso4,
  6. Angelika Diem5,
  7. Christian P Kratz6,
  8. Radovan Dvorsky7,
  9. Mohammad Reza Ahmadian7,8,
  10. Martin Zenker5
  1. 1Department of Human Genetics, University Medical Center St Radboud, Nijmegen, The Netherlands
  2. 2Department of Pathology, Wayne State University, Harper Hospital, Detroit, USA
  3. 3Department of Pediatrics, New York Methodist Hospital, Brooklyn, USA
  4. 4Department of Neurology and Laboratory of Neuropathology, Hospital de Santa Maria, Lisbon, Portugal
  5. 5Institute of Human Genetics, University of Erlangen-Nuremberg, Germany
  6. 6Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Germany
  7. 7Max-Planck-Institute of Molecular Physiology, Department of Structural Biology, Dortmund, Germany
  8. 8Institute of Biochemistry and Molecular Biology II, Heinrich-Heine-University Hospital, Düsseldorf, Germany
  1. Correspondence to:
 Martin Zenker
 Institute of Human Genetics, University of Erlangen-Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany; mzenker{at}


Background: Rare reports on patients with congenital myopathy with excess of muscle spindles (CMEMS), hypertrophic cardiomyopathy and variable features resembling Noonan syndrome have been published, but the genetic basis of this condition is so far unknown.

Methods and results: We analysed PTPN11 and RAS genes in five unrelated patients with this phenotype, and found HRAS mutations in four of them. Two disease-associated mutations, G12V and G12S, have previously been observed in patients with Costello syndrome (CS), and two other mutations, E63K and Q22K, are novel. All four mutations are predicted to enhance downstream HRas signalling, suggesting that CMEMS is a developmental consequence of sustained HRas activation in skeletal muscle.

Conclusion: This type of myopathy may represent a previously unrecogned manifestation of CS. However, some patients carrying HRAS mutations may exhibit prominent congenital muscular dysfunction, although features of CS may be less obvious, suggesting that germline HRAS mutations may underlie some cases of otherwise unclassified neonatal neuromuscular disorders.

  • CFC, cardio-facio-cutaneous syndrome
  • CMEMS, congenital myopathy with excess of muscle spindles
  • CS, Costello syndrome
  • NS, Noonan syndrome
  • HRAS
  • costello syndrome
  • noonan syndrome
  • myopathy
  • muscle spindle

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  • Published Online First 5 April 2007

  • Competing interests: None declared.