Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies

Abstract

Noonan syndrome is an autosomal dominant disease characterized by dysmorphic features, webbed neck, cardiac anomalies, short stature and cryptorchidism. It shows phenotypic overlap with Costello syndrome and cardio-facio-cutaneous (CFC) syndrome. Noonan syndrome and related disorders are caused by germline mutations in genes encoding molecules in the RAS/MAPK pathway. Recently, a gain-of-function mutation in SHOC2, p.S2G, has been identified as causative for a type of Noonan-like syndrome characterized by the presence of loose anagen hair. In order to understand the contribution of SHOC2 mutations to the clinical manifestations of Noonan syndrome and related disorders, we analyzed SHOC2 in 92 patients with Noonan syndrome and related disorders who did not exhibit PTPN11, KRAS, HRAS, BRAF, MAP2K1/2, SOS1 or RAF1 mutations. We found the previously identified p.S2G mutation in eight of our patients. We developed a rapid detection system to identify the p.S2G mutation using melting curve analysis, which will be a useful tool to screen for the apparently common mutation. All the patients with the p.S2G mutation showed short stature, sparse hair and atopic skin. Six of the mutationpositive patients showed severe mental retardation and easily pluckable hair, and one showed leukocytosis. No SHOC2 mutations were identified in leukemia cells from 82 leukemia patients. These results suggest that clinical manifestations in SHOC2 mutation-positive patients partially overlap with those in patients with typical Noonan or CFC syndrome and show that easily pluckable/loose anagen hair is distinctive in SHOC2 mutation-positive patients.

Phenotypic variability associated with the invariant SHOC2 c.4A>G (p.Ser2Gly) missense mutation

“…Intriguingly, some of these subjects were reported to have features suggestive of Costello syndrome, especially in early infancy. More recently, a number of reports confirmed the distinctive phenotype associated with the c.4A > G mutation, but also provided evidence for a wider clinical variability characterizing this disorder [Komatsuzaki et al, 2010;Digilio et al, 2011;Lee et al, 2011;Capalbo et al, 2012;Hoban et al, 2012;Gripp et al, 2013;Ş imşek-Kiper et al, 2013;Gargano et al, 2014;Zmolikova et al, 2014]. Table I summarizes the main clinical features of the SHOC2 cases reported in literature.…”

Recent advances in RASopathies

“…20 In two of the initial studies on this disorder, cardiac defects have been observed in 27 out of 33 (~80%) individuals. 20,59 Compared with individuals with NS, septal defects (~42%) and mitral valve anomalies (~31%) were more frequent. 20,59 In following case reports on individuals with the SHOC2 p.S2G mutation, phenotypic variability was noted.…”

Desmoglein-1/Erbin interaction suppresses ERK activation to support epidermal differentiation

“…The abnormally high concentration of SHOC2 now available to membrane-bound Ras translates into heightened ERK activity, an event believed to belie NS/LAH pathogenesis. Characterized by a range of cognitive and skeletal abnormalities, patients with NS/LAH also present with a number of cardiac and dermatological conditions, in many ways resembling those identified with genetic disorders stemming from mutant desmosomal proteins (93)(94)(95). NS/LAH symptoms like hyperkeratosis and abnormalities of palm and sole skin, in particular, are reminiscent of features associated with SPPK.…”