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

Cristina Digilio, Paola Daniele, Christina Lissewski, Gianfranco Bocchinfuso, Lorenzo Stella, Sylvie Odent, Nicole Philip, Laurence Faivre, Marketa Vlckova, Eva Seemanova, Maria Gnazzo, Martin Zenker, Giuseppe Zampino, Alain Verloes, Bruno Dallapiccola, Amy E Roberts, Hélène Cavé, Bruce D Gelb, Benjamin G Neel, Marco Tartaglia, Alessandro Bruselles, Jiani C Yin, Cecilia Gunnarsson, Carl Virtanen, Séverine Drunat, Francesca Lepri, Alessandro De Luca, Cesare Rossi, Andrea Ciolfi, Trevor J Pugh, Viviana Cordeddu, James R Priest, Len A Pennacchio, Zhibin Lu, Arnavaz Danesh, Rene Quevedo, Alaa Hamid, Simone Martinelli, Francesca Pantaleoni

Journal: Human mutation 2016;36(11):1080-7

PMID: 26173643

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Abstract

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.

Address: 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.; Princess Margaret Cancer Centre, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, ON, M5S, Canada.; Department of Clinical and Experimental Medicine, Division of Clinical Genetics, Faculty of Health Sciences, Linköping University, Linköping, 581 83, Sweden.; Département de Génétique, Hôpital Robert Debré, Paris, 75019, France.; Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, 00165, Italy.; IRCCS-Casa Sollievo della Sofferenza Hospital, Mendel Institute, Rome, 00161, Italy.; UO Genetica Medica, Policlinico S.Orsola-Malpighi, Bologna, 40138, 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.; Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma 'Tor Vergata', Rome, 00133, Italy.; Service de Génétique Clinique, Hôpital SUD, Rennes, 35200, France.; Département de Génétique Médicale, Hôpital d'Enfants de la Timone, Marseille 13385, France.; Centre de Génétique, Hôpital d'Enfants, Dijon, 21000, France.; Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, 150 06, Czech Republic.; Istituto di Pediatria, Università Cattolica del Sacro Cuore, Rome, 00168, Italy.; Department of Cardiology and Division of Genetics, Boston Children's Hospital, Boston, Massachusetts, 02115.; INSERM UMR_S1131, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris-Sorbonne-Cité, Paris, 75205, 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.; The Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, New York, 10016.

DOI: 10.1002/humu.22834

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MeSH Terms: Adolescent, Adult, Alleles, Amino Acid Substitution, Child, DNA Mutational Analysis, Exome, Facies, Female, Genetic Association Studies, Genotype, Humans, Male, Models, Molecular, Mutation, Noonan Syndrome, Phenotype, Protein Conformation, Protein Interaction Domains and Motifs, Son of Sevenless Proteins, Young Adult