Article Text

other Versions

PDF
SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome
  1. Martin Zenker (mzenker{at}humgenet.uni-erlangen.de)
  1. Institute of Human Genetics, Germany
    1. Denise Horn
    1. Institute of Medical Genetics, Charité, University Medicine of Berlin, Germany
      1. Dagmar Wieczorek
      1. Institut für Humangenetik, Universität Duisburg-Essen, Essen, Germany
        1. Judith Allanson
        1. Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
          1. Silke Pauli
          1. Institute of Human Genetics, University of Goettingen, Germany
            1. Ineke van der Burgt
            1. Department of Human Genetics, University Medical Center St Radboud, Nijmegen, Netherlands
              1. Helmuth-Guenther Doerr
              1. Department of Pediatric Endocrinology and Pediatric Cardiology, University Children's Hospital, Erla, Germany
                1. Harald Gaspar
                1. Institute of Medical Genetics, University of Zurich, Switzerland
                  1. Michael Hofbeck
                  1. University Children's Hospital, Pediatric Cardiology, Tuebingen, Germany
                    1. Gabriele Gillessen-Kaesbach
                    1. Institut für Humangenetik, Universitätsklinikum Schleswig-Holstein,, Germany
                      1. Andreas Koch
                      1. Department of Pediatric Cardiology, University Children's Hospital, Erlangen, Germany
                        1. Peter Meinecke
                        1. Medizinische Genetik, Altonaer Kinderkrankenhaus, Hamburg, Germany
                          1. Anja Nowak
                          1. Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
                            1. Anita Rauch
                            1. Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany
                              1. Silke Reif
                              1. Institut für Humangenetik und Medizinische Biologie, Universität Halle, Germany
                                1. Christian von Schnakenburg
                                1. Department of Pediatrics and Adolescent Medicine, University of Freiburg, Germany
                                  1. Heide Seidel
                                  1. Institute of Human Genetics, Ludwig-Maximilian University, Munich, Germany
                                    1. Lars-Erik Wehner
                                    1. Institute of Human Genetics, University of Goettingen, Germany
                                      1. Christiane Zweier
                                      1. Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany
                                        1. Susanne Bauhuber
                                        1. Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany
                                          1. Verena Matejas
                                          1. Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany
                                            1. Christian P Kratz
                                            1. Department of Pediatrics and Adolescent Medicine, University of Freiburg, Germany
                                              1. Christoph Thomas
                                              1. Max Planck Institute of Molecular Physiology, Department of Structural Biology, Dortmund, Germany
                                                1. Kerstin Kutsche
                                                1. Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

                                                  Abstract

                                                  Background: Heterozygous gain-of-function mutations in various genes encoding proteins of the Ras-MAPK signaling 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 discovery in patients with NS, however, 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, 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 individuals classified as CFCS was found to carry a pathogenic sequence change in this gene.

                                                  Conclusion: We 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 CFCS. These findings corroborate that, despite being caused by gain-of-function mutations in molecules belonging to the same pathway, NS and CFCS hardly overlap genotypically.

                                                  • Congenital heart defect
                                                  • Pulmonic stenosis
                                                  • Ras pathway
                                                  • Short stature

                                                  Statistics from Altmetric.com

                                                  Request permissions

                                                  If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.