title: Myopathy caused by HRAS germline mutations: implications for disturbed myogenic differentiation in the presence of constitutive HRas activation.
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 is so far unknown.
  
  
  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.
  
  
  CONCLUSIONS
  This type of myopathy may represent a previously unrecognized 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.
authors.forename: Ineke
authors.initials: I
authors.lastname: van der Burgt
authors.forename: William
authors.initials: W
authors.lastname: Kupsky
authors.forename: Stephani
authors.initials: S
authors.lastname: Stassou
authors.forename: Ali
authors.initials: A
authors.lastname: Nadroo
authors.forename: Cândida
authors.initials: C
authors.lastname: Barroso
authors.forename: Angelika
authors.initials: A
authors.lastname: Diem
authors.forename: Christian P
authors.initials: CP
authors.lastname: Kratz
authors.forename: Radovan
authors.initials: R
authors.lastname: Dvorsky
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Ahmadian
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009470:Muscle Spindles / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics
chemical_list: C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)