Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome
In: ISSN: 1059-7794, 2015
academicJournal
Zugriff:
International audience ; The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals. Here, we report that missense mutations altering Son of Sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology (DH) domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its autoinhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the DH domain
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Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome
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Autor/in / Beteiligte Person: | Cordeddu, Viviana ; Yin, Jiani C. ; Gunnarsson, Cecilia ; Virtanen, Carl ; Drunat, Séverine ; Lepri, Francesca ; de Luca, Alessandro ; Rossi, Cesare ; Ciolfi, Andrea ; Pugh, Trevor J. ; Bruselles, Alessandro ; Priest, James R. ; Pennacchio, Len A. ; Lu, Zhibin ; Danesh, Arnavaz ; Quevedo, Rene ; Hamid, Alaa ; Martinelli, Simone ; Pantaleoni, Francesca ; Gnazzo, Maria ; Daniele, Paola ; Lissewski, Christina ; Bocchinfuso, Gianfranco ; Stella, Lorenzo ; Odent, Sylvie ; Philip, Nicole ; Faivre, Laurence ; Vlckova, Marketa ; Seemanova, Eva ; Digilio, Cristina ; Zenker, Martin ; Zampino, Giuseppe ; Verloes, Alain ; Dallapiccola, Bruno ; Roberts, Amy E. ; Cavé, Hélène ; Gelb, Bruce D. ; Neel, Benjamin G. ; Tartaglia, Marco ; Linköping University (LIU) ; Département de génétique ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7) ; Mendel, Laboratorio ; Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza San Giovanni Rotondo (IRCCS) ; UO Genetica Medica ; S.Orsola-Malpighi, Policlinico ; Ematologia, Oncologia e Medicina Molecolare ; Istituto Superiore di Sanità = National Institute of Health (ISS) ; Dipartimento di Scienze e Tecnologie Chimiche ; Università degli Studi di Roma Tor Vergata Roma, Italia = University of Rome Tor Vergata Rome, Italy = Université de Rome Tor Vergata Rome, Italie ; Institut de Génétique et Développement de Rennes (IGDR) ; Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) ; Centre Hospitalier Universitaire de Rennes CHU Rennes = Rennes University Hospital Ponchaillou ; Service de Génétique ; Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Timone CHU - APHM (TIMONE) ; Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon) ; Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon) ; Institute of Human Genetics ; University Hospital Magdeburg ; Pediatrica, Clinica ; Università cattolica del Sacro Cuore Milano (Unicatt) ; Physiopathologie et neuroprotection des atteintes du cerveau en développement ; Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM) ; Medical Genetics and Pediatric Cardiology ; IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital ; Département de génétique Robert Debré ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré Paris ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP) ; R01 HL071207, National Institutes of Health |
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Zeitschrift: | ISSN: 1059-7794, 2015 |
Veröffentlichung: | HAL CCSD ; Wiley, 2015 |
Medientyp: | academicJournal |
DOI: | 10.1002/humu.22834 |
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