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Myopathy caused by HRAS germline mutations - implications for disturbed myogenic differentiation in the presence of constitutive H-Ras activation
  1. Ineke van der Burgt (i.vanderburgt{at}antrg.umcn.nl)
  1. Department of Human Genetics, University Medical Center St Radboud, Nijmegen, Netherlands
    1. William Kupsky
    1. Department of Pathology, Wayne State University, Harper Hospital, Detroit, United States
      1. Stephani Stassou
      1. Department of Pediatrics, New York Methodist Hospital, Brooklyn, United States
        1. Ali Nadroo
        1. Department of Pediatrics, New York Methodist Hospital, Brooklyn, United States
          1. Candida Barroso
          1. Department of Neurology and Laboratory of Neuropathology, Hospital de Santa Maria, Lisbon, Portugal
            1. Angelika Diem
            1. Institute of Human Genetics, University of Erlangen-Nuremberg, Germany
              1. Christian P Kratz
              1. Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Freiburg, Germany
                1. Radovan Dvorsky
                1. Max-Planck-Institute of Molecular Physiology, Department of Structural Biology, Dortmund, Germany
                  1. Mohammad Reza Ahmadian
                  1. Institute of Biochemistry and Molecular Biology II, Heinrich-Heine-University Hospital, Düsseld, Germany
                    1. Martin Zenker (mzenker{at}humgenet.uni-erlangen.de)
                    1. Institute of Human Genetics, University of Erlangen-Nuremberg, Germany

                      Abstract

                      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 has been unknown.

                      Methods and Results: We analyzed 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), while two other mutations, E63K and Q22K, are novel. All four mutations are predicted to enhance downstream H-Ras signaling, suggesting that CMEMS is a developmental consequence of sustained H-Ras activation in skeletal muscle.

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

                      • Costello syndrome
                      • HRAS
                      • Noonan syndrome
                      • congenital myopathy

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