Article

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

Journal of Medical Genetics (Impact Factor: 5.64). 11/2007; 44(10):651-6. DOI: 10.1136/jmg.2007.051276
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
136 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Noonan syndrome (NS) is an autosomal dominant disorder characterized by facial dysmorphisms, short stature and congenital heart defects. The disorder is genetically heterogeneous and shows clinical overlap with other RASopathies. These syndromes are caused by mutations in a variety of genes leading to dysregulation of the RAS-MAPK pathway: PTPN11, KRAS, SOS1, RAF1, CBL, SHOC2, NRAS, BRAF, MAP2K1, MAP2K2, HRAS, NF1 and SPRED1. In this study, we conduct a genotype-phenotype analysis of 33 patients with a clinical diagnosis of NS without a PTPN11 mutation. Mutation analysis of the genes involved in RASopathies was performed, except for NF1 and SPRED1. In 14 (42%) NS patients, a mutation was found, 7 (21%) had a mutation in SOS1, 3 (9%) in RAF1 and 1 (3%) in KRAS, MAP2K2, BRAF and SHOC2 each. The phenotype of these mutation-positive cases corresponded to that described in the literature. In the cases with a BRAF and MAP2K2 mutation, the diagnosis cardio-facio-cutaneous syndrome was made. The patient with the SHOC2 mutation had features compatible with 'Noonan-like syndrome with loose anagen hair'. Three major clinical features of NS - a typical face, short stature and a pulmonary valve stenosis - were less frequently present in the group without a mutation. Missense mutations in genes encoding proteins of the RAS-MAPK pathway cause NS. The 3 major clinical features of NS were less frequently present in the mutation-negative patients, which stresses the importance of the syndrome-specific symptoms of the face, heart and short stature in NS. However, all mutation-negative cases met the NS criteria, indicating that the involvement of novel genes is to be expected.
    Molecular syndromology 06/2013; 4(5):227-34. DOI:10.1159/000350686
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The Ras-MAPK signaling pathway is highly conserved throughout evolution and is activated downstream of a wide range of receptor stimuli. Ras guanine nucleotide exchange factors (RasGEFs) catalyze GTP loading of Ras and play a pivotal role in regulating receptor-ligand induced Ras activity. In T cells, three families of functionally important RasGEFs are expressed: RasGRF, RasGRP, and Son of Sevenless (SOS)-family GEFs. Early on it was recognized that Ras activation is critical for T cell development and that the RasGEFs play an important role herein. More recent work has revealed that nuances in Ras activation appear to significantly impact T cell development and selection. These nuances include distinct biochemical patterns of analog versus digital Ras activation, differences in cellular localization of Ras activation, and intricate interplays between the RasGEFs during distinct T cell developmental stages as revealed by various new mouse models. In many instances, the exact nature of these nuances in Ras activation or how these may result from fine-tuning of the RasGEFs is not understood. One large group of biomolecules critically involved in the control of RasGEFs functions are lipid second messengers. Multiple, yet distinct lipid products are generated following T cell receptor (TCR) stimulation and bind to different domains in the RasGRP and SOS RasGEFs to facilitate the activation of the membrane-anchored Ras GTPases. In this review we highlight how different lipid-based elements are generated by various enzymes downstream of the TCR and other receptors and how these dynamic and interrelated lipid products may fine-tune Ras activation by RasGEFs in developing T cells.
    Frontiers in Immunology 01/2013; 4:239. DOI:10.3389/fimmu.2013.00239
  • [Show abstract] [Hide abstract]
    ABSTRACT: Noonan syndrome (NS) and related disorders, which are now summarized under the term RASopathies, are caused by germline mutations in genes encoding protein components of the Ras/mitogen-activated protein kinase pathway. In this study, we evaluated the clinical and molecular spectrum of 21 Tunisian patients, recruited by a cardiology unit, for whom RASopathy diagnosis was suspected by clinical geneticists. Overall, 19 patients had a clinical diagnosis of NS and 2 were classified as having Cardiofaciocutaneous (CFC) syndrome. In 52% (n = 11) of patients, a RASopathy has been molecularly confirmed. Mutations in PTPN11 and SOS1 genes were found in patients with diagnosis of NS and BRAF gene mutations in patients with CFC syndrome. As reported from other cohorts, mutations in exons 3 and 8 of the PTPN11 gene predominated in Tunisian NS patients. A very uncommon PTPN11 mutation c.5C>T (p.T2I), the functional consequences of which have so far remained unclear, was identified in one patient. As biased by the mode of recruitment, all patients included in this study had a congenital heart defect, with pulmonary valve stenosis being the most frequent one. Short stature and developmental abnormalities were present in mutation-positive cases. This is the first molecular study in patients from southern Tunisia with RASopathy diagnosis.
    Molecular syndromology 05/2014; DOI:10.1159/000362898

Full-text (2 Sources)

Download
48 Downloads
Available from
Jun 3, 2014