Activating mutations in v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) have recently been identified as the molecular cause underlying Costello syndrome (CS). To further investigate the phenotypic spectrum associated with germline HRAS mutations and characterize their molecular diversity, subjects with a diagnosis of CS (N = 9), Noonan syndrome (NS; N = 36), cardiofaciocutaneous syndrome (CFCS; N = 4), or with a phenotype suggestive of these conditions but without a definitive diagnosis (N = 12) were screened for the entire coding sequence of the gene. A de novo heterozygous HRAS change was detected in all the subjects diagnosed with CS, while no lesion was observed with any of the other phenotypes. While eight cases shared the recurrent c.34G>A change, a novel c.436G>A transition was observed in one individual. The latter affected residue, p.Ala146, which contributes to guanosine triphosphate (GTP)/guanosine diphosphate (GDP) binding, defining a novel class of activating HRAS lesions that perturb development. Clinical characterization indicated that p.Gly12Ser was associated with a homogeneous phenotype. By analyzing the genomic region flanking the HRAS mutations, we traced the parental origin of lesions in nine informative families and demonstrated that de novo mutations were inherited from the father in all cases. We noted an advanced age at conception in unaffected fathers transmitting the mutation.
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"Specific amino acid substitutions, particularly those strongly inducing oncogenic cell transformation, may result in an early lethal phenotype [Lo et al., 2008]. In contrast, rarer HRAS mutations are associated with an attenuated phenotype as reported for p.Thr58 and p.Ala146 [Zampino et al., 2007; Gripp et al., 2008, 2012a], or a slightly variant phenotype with p.Glu37dup [Gremer et al., 2010a]. HRAS serves as signal transducer by alternating between an active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)-bound state. "
"Similarly to what is observed in CS, caused by a narrow spectrum of missense HRAS mutations [Aoki et al., 2005; Estepp et al., 2006; Gripp et al., 2006; Zampino et al., 2007], such phenotypic homogeneity reflects the genetic homogeneity of this disorder, with all cases being associated with the c.4A>G change [Cordeddu et al., 2009; Komatsuzaki et al., 2010; Gripp et al., 2013]. So far, less than 50 SHOC2 mutation-positive patients have been reported [Cordeddu et al., 2009; Komatsuzaki et al., 2010; Baldassarre et al., 2014; Gargano et al., 2014; Takenouchi et al., 2014; Zmolikova et al., 2014], with malignancies documented in two [Ekvall et al., 2011; Gripp et al., 2013]. "
"Mutations generally affect Gly 12 and result in enhanced signal flow through the MAPK and PI3K-AKT signaling cascades [Rosenberger et al., 2009]. Accordingly , CS belongs to the so-called RAS opathies, a group of clinically related developmental disorders sharing reduced linear growth, dysmorphic facial features, congenital heart defects, skeletal and ectodermal anomalies, and a variable degree of cognitive deficits [Tartaglia and Gelb, 2005, 2010; Estep et al., 2006; Gripp et al., 2006; Kerr et al., 2006; Kratz et al., 2007; Schubbert et al., 2007; Zampino et al., 2007; Rauen, 2013]. "