Myopathy caused by HRAS germline mutations: implications for disturbed myogenic differentiation in the presence of constitutive HRas activation.
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.
van der Burgt
Ineke
I
Kupsky
William
W
Stassou
Stephani
S
Nadroo
Ali
A
Barroso
Cândida
C
Diem
Angelika
A
Kratz
Christian P
CP
Dvorsky
Radovan
R
Ahmadian
Mohammad Reza
MR
Zenker
Martin
M
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
C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)