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dc.contributor.authorLepri, Francesca
dc.contributor.authorDe Luca, Alessandro
dc.contributor.authorStella, Lorenzo
dc.contributor.authorRossi, Cesare
dc.contributor.authorBaldassarre, Giuseppina
dc.contributor.authorPantaleoni, Francesca
dc.contributor.authorCordeddu, Viviana
dc.contributor.authorWilliams, Bradley J.
dc.contributor.authorDentici, Maria L.
dc.contributor.authorCaputo, Viviana
dc.contributor.authorVenanzi, Serenella
dc.contributor.authorBonaguro, Michela
dc.contributor.authorKavamura, Ines [UNIFESP]
dc.contributor.authorFaienza, Maria F.
dc.contributor.authorPilotta, Alba
dc.contributor.authorStanzial, Franco
dc.contributor.authorFaravelli, Francesca
dc.contributor.authorGabrielli, Orazio
dc.contributor.authorMarino, Bruno
dc.contributor.authorNeri, Giovanni
dc.contributor.authorSilengo, Margherita Cirillo
dc.contributor.authorFerrero, Giovanni B.
dc.contributor.authorTorrrente, Isabella
dc.contributor.authorSelicorni, Angelo
dc.contributor.authorMazzanti, Laura
dc.contributor.authorDigilio, Maria C.
dc.contributor.authorZampino, Giuseppe
dc.contributor.authorDallapiccola, Bruno
dc.contributor.authorGelb, Bruce D.
dc.contributor.authorTartaglia, Marco
dc.identifier.citationHuman Mutation. Hoboken: Wiley-Blackwell, v. 32, n. 7, p. 760-772, 2011.
dc.description.abstractNoonan 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.en
dc.description.sponsorshipERA-Net for research programs on rare diseases 2009 (European network on Noonan Syndrome and related disorders)
dc.description.sponsorshipAssociazione Italiana Sindromi di Costello e Cardiofaciocutanea
dc.description.sponsorshipItalian Ministry of Health
dc.description.sponsorshipItalian Ministry of Education, University and Research
dc.relation.ispartofHuman Mutation
dc.rightsAcesso aberto
dc.subjectNoonan syndromeen
dc.subjectmutation analysisen
dc.subjectstructural analysisen
dc.subjectgenotype-phenotype correlationsen
dc.titleSOS1 Mutations in Noonan Syndrome: Molecular Spectrum, Structural Insights on Pathogenic Effects, and Genotype-Phenotype Correlationsen
dc.contributor.institutionIst Super Sanita
dc.contributor.institutionIRCCS Casa Sollievo Sofferenza
dc.contributor.institutionUniv Roma Tor Vergata
dc.contributor.institutionSt Orsola Marcello Malpighi Hosp
dc.contributor.institutionUniv Turin
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.contributor.institutionUniv Bari
dc.contributor.institutionOsped Pediat
dc.contributor.institutionOsped Bolzano
dc.contributor.institutionOspedali Galliera
dc.contributor.institutionUniv Politecn Marche
dc.contributor.institutionUniv Roma La Sapienza
dc.contributor.institutionUniv Cattolica Sacro Cuore
dc.contributor.institutionUniv Milano Bicocca
dc.contributor.institutionUniv Bologna
dc.contributor.institutionMt Sinai Sch Med
dc.description.affiliationIst Super Sanita, Dept Hematol Oncol & Mol Med, I-00161 Rome, Italy
dc.description.affiliationIRCCS Casa Sollievo Sofferenza, Lab Mendel, San Giovanni Rotondo, Italy
dc.description.affiliationUniv Roma Tor Vergata, Dipartimento Sci & Tecnol Chim, Rome, Italy
dc.description.affiliationSt Orsola Marcello Malpighi Hosp, UO Genet Med, Bologna, Italy
dc.description.affiliationUniv Turin, Dipartimento Pediat, Turin, Italy
dc.description.affiliationGeneDx, Gaithersburg, MD USA
dc.description.affiliationUniversidade Federal de São Paulo, São Paulo, Brazil
dc.description.affiliationUniv Bari, Dept Biomed Dev Age, Bari, Italy
dc.description.affiliationOsped Pediat, Brescia, Italy
dc.description.affiliationOsped Bolzano, Serv Aziendale Consulenza Genet, Bolzano, Italy
dc.description.affiliationOspedali Galliera, SC Genet Umana, Genoa, Italy
dc.description.affiliationUniv Politecn Marche, Ist Sci Materno Infantili, Ancona, Italy
dc.description.affiliationUniv Roma La Sapienza, Dept Pediat, Div Pediat Cardiol, Rome, Italy
dc.description.affiliationUniv Cattolica Sacro Cuore, Ist Genet Med, Rome, Italy
dc.description.affiliationUniv Milano Bicocca, AOS Gerardo Fdn MBBM, Pediat Clin, Monza, Italy
dc.description.affiliationUniv Bologna, Dipartimento Pediat, Bologna, Italy
dc.description.affiliationIRCCS, Osped Pediat Bambino Gesu, Rome, Italy
dc.description.affiliationUniv Cattolica Sacro Cuore, Ist Clin Pediat, Rome, Italy
dc.description.affiliationMt Sinai Sch Med, Child Hlth & Dev Inst, New York, NY USA
dc.description.affiliationUnifespUniversidade Federal de São Paulo, São Paulo, Brazil
dc.description.sponsorshipIDTelethon-Italy: GGP07115
dc.description.sponsorshipIDTelethon-Italy: GGP10020
dc.description.sponsorshipIDNIH: HL71207
dc.description.sponsorshipIDItalian Ministry of Health: RC2009
dc.description.sponsorshipIDItalian Ministry of Health: RC2010
dc.description.sponsorshipIDItalian Ministry of Education, University and Research: FIRB RBIP06PMF2_005
dc.description.sourceWeb of Science
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