TY - JOUR T1 - Myopathy caused by <em>HRAS</em> germline mutations: implications for disturbed myogenic differentiation in the presence of constitutive HRas activation JF - Journal of Medical Genetics JO - J Med Genet SP - 459 LP - 462 DO - 10.1136/jmg.2007.049270 VL - 44 IS - 7 AU - Ineke van der Burgt AU - William Kupsky AU - Stephani Stassou AU - Ali Nadroo AU - Cândida Barroso AU - Angelika Diem AU - Christian P Kratz AU - Radovan Dvorsky AU - Mohammad Reza Ahmadian AU - Martin Zenker Y1 - 2007/07/01 UR - http://jmg.bmj.com/content/44/7/459.abstract N2 - 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. ER -