SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome

University of Duisburg-Essen, Essen, North Rhine-Westphalia, Germany
Journal of Medical Genetics (Impact Factor: 6.34). 11/2007; 44(10):651-6. DOI: 10.1136/jmg.2007.051276
Source: PubMed


Heterozygous gain-of-function mutations in various genes encoding proteins of the Ras-MAPK signalling cascade have been identified as the genetic basis of Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFCS). Mutations of SOS1, the gene encoding a guanine nucleotide exchange factor for Ras, have been the most recent discoveries in patients with NS, but this gene has not been studied in patients with CFCS.
We investigated SOS1 in a large cohort of patients with disorders of the NS-CFCS spectrum, who had previously tested negative for mutations in PTPN11, KRAS, BRAF, MEK1 and MEK2. Missense mutations of SOS1 were discovered in 28% of patients with NS. In contrast, none of the patients classified as having CFCS was found to carry a pathogenic sequence change in this gene.
We have confirmed SOS1 as the second major gene for NS. Patients carrying mutations in this gene have a distinctive phenotype with frequent ectodermal anomalies such as keratosis pilaris and curly hair. However, the clinical picture associated with SOS1 mutations is different from that of CFCS. These findings corroborate that, despite being caused by gain-of-function mutations in molecules belonging to the same pathway, NS and CFCS scarcely overlap genotypically.

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Available from: Andreas M E Koch
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    • "PTPN11 mutations are significantly associated with the presence of pulmonic stenosis, short stature, easy bruising and thorax deformities [Zenker et al., 2004]. Patients with SOS1 mutations often present with pulmonary valve disease and ectodermal abnormalities, including facial keratosis pilaris, sparse eyebrows and curly hair [Roberts et al., 2007; Tartaglia et al., 2007; Zenker et al., 2007a]. "
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    ABSTRACT: Noonan syndrome is a genetically heterogeneous disorder caused by mutations in PTPN11, SOS1, RAF1 and less frequently in KRAS, NRAS or SHOC2. Here, we performed mutation analysis of NRAS and SHOC2 in 115 PTPN11, SOS1, RAF1, and KRAS mutation-negative individuals. No SHOC2 mutations were found, but we identified 3 NRAS mutations in 3 probands. One NRAS mutation was novel. The phenotype associated with germline NRAS mutations is variable. Our results confirm that a small proportion of Noonan syndrome patients carry germline NRAS mutations.
    Full-text · Article · Jun 2012 · Molecular syndromology
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    • "None of the affected with confirmed SOS-1 mutations described to date, presented with GF or was predisposed to the development of tumors. Furthermore, the mutations described are not associated with any type of tumor (Tartaglia et al., 2007, Roberts et al., 2007, Zenker et al., 2007). There were no further observations of HGF due to SOS-1 mutations. "

    Full-text · Chapter · Sep 2011
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    • "In these subjects, however, cognitive deficits are generally absent or minor [Denayer et al., 2010; Narumi et al., 2008; Tartaglia et al., 2007; Zenker et al., 2007a; present study]. Consistent with these observations, our mutational screening on a clinically well-characterized CFCS cohort failed in identifying any SOS1 mutation, confirming a previous survey indicating that SOS1 does not represent a major gene for this disorder [Zenker et al. 2007a]. Atlhough the clinical features of SOS1 mutation-positive subjects appear to be less severe compared to what is generally observed in CFCS, the identification of subjects with an ''overlapping'' phenotype suggests that a clinical continuum might be associated with defects in SOS1, as previously documented for other disease genes implicated in RAS-opathies [Sarkozy et al., 2009a; Zenker et al., 2007b]. "
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    ABSTRACT: Noonan syndrome (NS) is among the most common nonchromosomal disorders affecting development and growth. NS is caused by aberrant RAS-MAPK signaling and is genetically heterogeneous, which explains, in part, the marked clinical variability documented for this Mendelian trait. Recently, we and others identified SOS1 as a major gene underlying NS. Here, we explored further the spectrum of SOS1 mutations and their associated phenotypic features. Mutation scanning of the entire SOS1 coding sequence allowed the identification of 33 different variants deemed to be of pathological significance, including 16 novel missense changes and in-frame indels. Various mutation clusters destabilizing or altering orientation of regions of the protein predicted to contribute structurally to the maintenance of autoinhibition were identified. Two previously unappreciated clusters predicted to enhance SOS1's recruitment to the plasma membrane, thus promoting a spatial reorientation of domains contributing to inhibition, were also recognized. Genotype-phenotype analysis confirmed our previous observations, establishing a high frequency of ectodermal anomalies and a low prevalence of cognitive impairment and reduced growth. Finally, mutation analysis performed on cohorts of individuals with nonsyndromic pulmonic stenosis, atrial septal defects, and ventricular septal defects excluded a major contribution of germline SOS1 lesions to the isolated occurrence of these cardiac anomalies.
    Full-text · Article · Jul 2011 · Human Mutation
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