1. SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations
- Author
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Francesca Faravelli, Margherita Silengo, Giovanni Battista Ferrero, Ines Kavamura, Orazio Gabrielli, Marco Tartaglia, Serenella Venanzi, Angelo Selicorni, Franco Stanzial, Lorenzo Stella, Michela Bonaguro, Giuseppe Zampino, Laura Mazzanti, Bruce D. Gelb, Maria Cristina Digilio, Maria Lisa Dentici, Giuseppina Baldassarre, Francesca Romana Lepri, Cesare Rossi, Francesca Pantaleoni, Viviana Cordeddu, Maria Felicia Faienza, Viviana Caputo, Bradley Williams, Alessandro De Luca, Alba Pilotta, Bruno Dallapiccola, Bruno Marino, Giovanni Neri, Isabella Torrrente, Laboratorio Mendel, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Dipartimento di Scienze e Tecnologie Chimiche, Università degli Studi di Roma Tor Vergata [Roma], UO Genetica Medica, Policlinico S.Orsola-Malpighi, Pediatria, Università degli studi di Torino (UNITO), Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanita', GeneDx [Gaithersburg, MD, USA], Ematologia, Oncologia, Medicina Molecolare, Medical Genetics, Federal University of Sao Paulo, Department of Biomedicine of Developmental Age, Università degli studi di Bari Aldo Moro (UNIBA), Auxoendocrinologia, Ospedale Pediatrico, Servizio aziendale di Consulenza Genetica, Ospedale di Bolzano, Department of Human Genetics, Galliera Hospital, Istituto di Scienze Materno-Infantili, Università Politecnica delle Marche [Ancona] (UNIVPM), Policlinico 'Umberto I', Universita' 'La Sapienza', Universita Cattolica del Sacro Cuore, Università cattolica del Sacro Cuore [Milano] (Unicatt), Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), Università di Bologna, Policlinico S. Orsola-Malpighi, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Clinica Pediatrica, Pediatrics and Human Genetics, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Lepri F, De Luca A, Stella L, Rossi C, Baldassarre G, Pantaleoni F, Cordeddu V, Williams BJ, Dentici ML, Caputo V, Venanzi S, Bonaguro M, Kavamura I, Faienza MF, Pilotta A, Stanzial F, Faravelli F, Gabrielli O, Marino B, Neri G, Silengo MC, Ferrero GB, Torrrente I, Selicorni A, Mazzanti L, Digilio MC, Zampino G, Dallapiccola B, Gelb BD, Tartaglia M., Ist Super Sanita, IRCCS Casa Sollievo Sofferenza, Univ Roma Tor Vergata, St Orsola Marcello Malpighi Hosp, Univ Turin, GeneDx, Universidade Federal de São Paulo (UNIFESP), Univ Bari, Osped Pediat, Osped Bolzano, Ospedali Galliera, Univ Politecn Marche, Univ Roma La Sapienza, Univ Cattolica Sacro Cuore, Univ Milano Bicocca, Univ Bologna, IRCCS, and Mt Sinai Sch Med
- Subjects
Heart Septal Defects, Ventricular ,Male ,genotype-phenotype correlations ,Protein Conformation ,SOS1 MUTATIONS ,mutation analysis ,noonan syndrome ,ns ,sos1 ,structural analysis ,medicine.disease_cause ,Heart Septal Defects, Atrial ,INDEL Mutation ,Missense mutation ,Noonan syndrome ,SOS1 ,Child ,Genetics (clinical) ,Settore CHIM/02 - Chimica Fisica ,Genetics ,0303 health sciences ,Mutation ,030305 genetics & heredity ,NOONAN SYNDOME ,Life Sciences ,Exons ,Phenotype ,Major gene ,Pulmonary Valve Stenosis ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Female ,SOS1 Protein ,Research Article ,Adult ,Adolescent ,Mutation, Missense ,Biology ,NS ,Atrial septal defects ,genotype–phenotype correlations ,RAS-MAPK PATHWAY ,03 medical and health sciences ,medicine ,Humans ,Genetic Association Studies ,030304 developmental biology ,Mitogen-Activated Protein Kinase Kinases ,Genetic heterogeneity ,medicine.disease ,Introns - Abstract
Telethon-Italy ERA-Net for research programs on rare diseases 2009 (European network on Noonan Syndrome and related disorders) Associazione Italiana Sindromi di Costello e Cardiofaciocutanea NIH Italian Ministry of Health Italian Ministry of Education, University and Research Noonan syndrome (NS) is among the most common nonchromosomal disorders affecting development and growth. NS is caused by aberrant RAS-MAPK signaling and is genetically heterogeneous, which explains, in part, the marked clinical variability documented for this Mendelian trait. Recently, we and others identified SOS1 as a major gene underlying NS. Here, we explored further the spectrum of SOS1 mutations and their associated phenotypic features. Mutation scanning of the entire SOS1 coding sequence allowed the identification of 33 different variants deemed to be of pathological significance, including 16 novel missense changes and in-frame indels. Various mutation clusters destabilizing or altering orientation of regions of the protein predicted to contribute structurally to the maintenance of autoinhibition were identified. Two previously unappreciated clusters predicted to enhance SOS1's recruitment to the plasma membrane, thus promoting a spatial reorientation of domains contributing to inhibition, were also recognized. Genotype-phenotype analysis confirmed our previous observations, establishing a high frequency of ectodermal anomalies and a low prevalence of cognitive impairment and reduced growth. Finally, mutation analysis performed on cohorts of individuals with nonsyndromic pulmonic stenosis, atrial septal defects, and ventricular septal defects excluded a major contribution of germline SOS1 lesions to the isolated occurrence of these cardiac anomalies. Hum Mutat 32:760-772, 2011. (C) 2011 Wiley-Liss, Inc. Ist Super Sanita, Dept Hematol Oncol & Mol Med, I-00161 Rome, Italy IRCCS Casa Sollievo Sofferenza, Lab Mendel, San Giovanni Rotondo, Italy Univ Roma Tor Vergata, Dipartimento Sci & Tecnol Chim, Rome, Italy St Orsola Marcello Malpighi Hosp, UO Genet Med, Bologna, Italy Univ Turin, Dipartimento Pediat, Turin, Italy GeneDx, Gaithersburg, MD USA Universidade Federal de São Paulo, São Paulo, Brazil Univ Bari, Dept Biomed Dev Age, Bari, Italy Osped Pediat, Brescia, Italy Osped Bolzano, Serv Aziendale Consulenza Genet, Bolzano, Italy Ospedali Galliera, SC Genet Umana, Genoa, Italy Univ Politecn Marche, Ist Sci Materno Infantili, Ancona, Italy Univ Roma La Sapienza, Dept Pediat, Div Pediat Cardiol, Rome, Italy Univ Cattolica Sacro Cuore, Ist Genet Med, Rome, Italy Univ Milano Bicocca, AOS Gerardo Fdn MBBM, Pediat Clin, Monza, Italy Univ Bologna, Dipartimento Pediat, Bologna, Italy IRCCS, Osped Pediat Bambino Gesu, Rome, Italy Univ Cattolica Sacro Cuore, Ist Clin Pediat, Rome, Italy Mt Sinai Sch Med, Child Hlth & Dev Inst, New York, NY USA Universidade Federal de São Paulo, EPM, São Paulo, Brazil Telethon-Italy: GGP07115 Telethon-Italy: GGP10020 NIH: HL71207 Italian Ministry of Health: RC2009 Italian Ministry of Health: RC2010 Italian Ministry of Education, University and Research: FIRB RBIP06PMF2_005 Web of Science
- Published
- 2010
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