Ontology highlight
ABSTRACT: Background
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.Methods and results
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.Conclusion
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.
SUBMITTER: Zenker M
PROVIDER: S-EPMC2597961 | biostudies-literature | 2007 Oct
REPOSITORIES: biostudies-literature
Zenker Martin M Horn Denise D Wieczorek Dagmar D Allanson Judith J Pauli Silke S van der Burgt Ineke I Doerr Helmuth-Guenther HG Gaspar Harald H Hofbeck Michael M Gillessen-Kaesbach Gabriele G Koch Andreas A Meinecke Peter P Mundlos Stefan S Nowka Anja A Rauch Anita A Reif Silke S von Schnakenburg Christian C Seidel Heide H Wehner Lars-Erik LE Zweier Christiane C Bauhuber Susanne S Matejas Verena V Kratz Christian P CP Thomas Christoph C Kutsche Kerstin K
Journal of medical genetics 20070623 10
<h4>Background</h4>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.<h4>Methods and results</h4>We investigated SOS1 in a large co ...[more]