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Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome

V. Cordeddu, JC. Yin, C. Gunnarsson, C. Virtanen, S. Drunat, F. Lepri, A. De Luca, C. Rossi, A. Ciolfi, TJ. Pugh, A. Bruselles, JR. Priest, LA. Pennacchio, Z. Lu, A. Danesh, R. Quevedo, A. Hamid, S. Martinelli, F. Pantaleoni, M. Gnazzo, P....

. 2015 ; 36 (11) : 1080-7. [pub] 20150803

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc16028369

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.

Bambino Gesù Children's Hospital Istituto di Ricovero e Cura a Carattere Scientifico Rome 00165 Italy

Centre de Génétique Hôpital d'Enfants Dijon 21000 France

Département de Génétique Hôpital Robert Debré Paris 75019 France

Département de Génétique Hôpital Robert Debré Paris 75019 France INSERM UMR_S1131 Institut Universitaire d'Hématologie Université Paris Diderot Paris Sorbonne Cité Paris 75205 France

Département de Génétique Médicale Hôpital d'Enfants de la Timone Marseille 13385 France

Department of Biology and Medical Genetics Charles University 2nd Faculty of Medicine and University Hospital Motol Prague 150 06 Czech Republic

Department of Cardiology and Division of Genetics Boston Children's Hospital Boston Massachusetts 02115

Department of Clinical and Experimental Medicine Division of Clinical Genetics Faculty of Health Sciences Linköping University Linköping 581 83 Sweden

Dipartimento di Ematologia Oncologia e Medicina Molecolare Istituto Superiore di Sanità Rome 00161 Italy

Dipartimento di Ematologia Oncologia e Medicina Molecolare Istituto Superiore di Sanità Rome 00161 Italy Bambino Gesù Children's Hospital Istituto di Ricovero e Cura a Carattere Scientifico Rome 00165 Italy

Dipartimento di Ematologia Oncologia e Medicina Molecolare Istituto Superiore di Sanità Rome 00161 Italy Dipartimento di Scienze Psicologiche della Salute e del Territorio Università degli Studi G d'Annunzio Chieti Pescara 66100 Italy

Dipartimento di Scienze e Tecnologie Chimiche Università di Roma 'Tor Vergata' Rome 00133 Italy

Division of Pediatric Cardiology Stanford University School of Medicine Stanford University Stanford California 94305 Child Health Research Institute Stanford Cardiovascular Institute Stanford University School of Medicine Stanford California 94305

Genomics Division Lawrence Berkeley National Laboratory Berkeley California 94720 US Department of Energy Joint Genome Institute Walnut Creek California 94598

Institute of Human Genetics University Hospital of Magdeburg Otto von Guericke University Magdeburg 39106 Germany

IRCCS Casa Sollievo della Sofferenza Hospital Mendel Institute Rome 00161 Italy

Istituto di Pediatria Università Cattolica del Sacro Cuore Rome 00168 Italy

Princess Margaret Cancer Centre University Health Network and Department of Medical Biophysics University of Toronto Toronto Ontario ON M5S Canada

Princess Margaret Cancer Centre University Health Network and Department of Medical Biophysics University of Toronto Toronto Ontario ON M5S Canada The Laura and Isaac Perlmutter Cancer Center New York University School of Medicine New York New York 10016

Service de Génétique Clinique Hôpital SUD Rennes 35200 France

The Mindich Child Health and Development Institute and the Departments of Pediatrics and Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York New York 10029

UO Genetica Medica Policlinico S Orsola Malpighi Bologna 40138 Italy

Citace poskytuje Crossref.org

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