SOS1 Mutations in Noonan Syndrome: Molecular Spectrum, Structural Insights on Pathogenic Effects, and Genotype-Phenotype Correlations
Autor(a) principal: | |
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Data de Publicação: | 2011 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNIFESP |
Texto Completo: | http://repositorio.unifesp.br/handle/11600/33809 http://dx.doi.org/10.1002/humu.21492 |
Resumo: | 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. |
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Lepri, FrancescaDe Luca, AlessandroStella, LorenzoRossi, CesareBaldassarre, GiuseppinaPantaleoni, FrancescaCordeddu, VivianaWilliams, Bradley J.Dentici, Maria L.Caputo, VivianaVenanzi, SerenellaBonaguro, MichelaKavamura, Ines [UNIFESP]Faienza, Maria F.Pilotta, AlbaStanzial, FrancoFaravelli, FrancescaGabrielli, OrazioMarino, BrunoNeri, GiovanniSilengo, Margherita CirilloFerrero, Giovanni B.Torrrente, IsabellaSelicorni, AngeloMazzanti, LauraDigilio, Maria C.Zampino, GiuseppeDallapiccola, BrunoGelb, Bruce D.Tartaglia, MarcoIst Super SanitaIRCCS Casa Sollievo SofferenzaUniv Roma Tor VergataSt Orsola Marcello Malpighi HospUniv TurinGeneDxUniversidade Federal de São Paulo (UNIFESP)Univ BariOsped PediatOsped BolzanoOspedali GallieraUniv Politecn MarcheUniv Roma La SapienzaUniv Cattolica Sacro CuoreUniv Milano BicoccaUniv BolognaIRCCSMt Sinai Sch Med2016-01-24T14:16:54Z2016-01-24T14:16:54Z2011-07-01Human Mutation. Hoboken: Wiley-Blackwell, v. 32, n. 7, p. 760-772, 2011.1059-7794http://repositorio.unifesp.br/handle/11600/33809http://dx.doi.org/10.1002/humu.21492WOS000292551800009.pdf10.1002/humu.21492WOS:000292551800009Noonan 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.Telethon-ItalyERA-Net for research programs on rare diseases 2009 (European network on Noonan Syndrome and related disorders)Associazione Italiana Sindromi di Costello e CardiofaciocutaneaNIHItalian Ministry of HealthItalian Ministry of Education, University and ResearchIst Super Sanita, Dept Hematol Oncol & Mol Med, I-00161 Rome, ItalyIRCCS Casa Sollievo Sofferenza, Lab Mendel, San Giovanni Rotondo, ItalyUniv Roma Tor Vergata, Dipartimento Sci & Tecnol Chim, Rome, ItalySt Orsola Marcello Malpighi Hosp, UO Genet Med, Bologna, ItalyUniv Turin, Dipartimento Pediat, Turin, ItalyGeneDx, Gaithersburg, MD USAUniversidade Federal de São Paulo, São Paulo, BrazilUniv Bari, Dept Biomed Dev Age, Bari, ItalyOsped Pediat, Brescia, ItalyOsped Bolzano, Serv Aziendale Consulenza Genet, Bolzano, ItalyOspedali Galliera, SC Genet Umana, Genoa, ItalyUniv Politecn Marche, Ist Sci Materno Infantili, Ancona, ItalyUniv Roma La Sapienza, Dept Pediat, Div Pediat Cardiol, Rome, ItalyUniv Cattolica Sacro Cuore, Ist Genet Med, Rome, ItalyUniv Milano Bicocca, AOS Gerardo Fdn MBBM, Pediat Clin, Monza, ItalyUniv Bologna, Dipartimento Pediat, Bologna, ItalyIRCCS, Osped Pediat Bambino Gesu, Rome, ItalyUniv Cattolica Sacro Cuore, Ist Clin Pediat, Rome, ItalyMt Sinai Sch Med, Child Hlth & Dev Inst, New York, NY USAUniversidade Federal de São Paulo, EPM, São Paulo, BrazilTelethon-Italy: GGP07115Telethon-Italy: GGP10020NIH: HL71207Italian Ministry of Health: RC2009Italian Ministry of Health: RC2010Italian Ministry of Education, University and Research: FIRB RBIP06PMF2_005Web of Science760-772engWiley-BlackwellHuman Mutationhttp://olabout.wiley.com/WileyCDA/Section/id-406071.htmlinfo:eu-repo/semantics/openAccessNoonan syndromeNSSOS1mutation analysisstructural analysisgenotype-phenotype correlationsSOS1 Mutations in Noonan Syndrome: Molecular Spectrum, Structural Insights on Pathogenic Effects, and Genotype-Phenotype Correlationsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlereponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESPORIGINALWOS000292551800009.pdfapplication/pdf601951${dspace.ui.url}/bitstream/11600/33809/1/WOS000292551800009.pdfa27c0451210b5cde489cb2b901931a37MD51open accessTEXTWOS000292551800009.pdf.txtWOS000292551800009.pdf.txtExtracted texttext/plain84763${dspace.ui.url}/bitstream/11600/33809/2/WOS000292551800009.pdf.txtd05fa3b6dab7c176c92a03812a19bd14MD52open access11600/338092022-11-04 15:45:37.172open accessoai:repositorio.unifesp.br:11600/33809Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestopendoar:34652023-05-25T12:29:49.538083Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false |
dc.title.en.fl_str_mv |
SOS1 Mutations in Noonan Syndrome: Molecular Spectrum, Structural Insights on Pathogenic Effects, and Genotype-Phenotype Correlations |
title |
SOS1 Mutations in Noonan Syndrome: Molecular Spectrum, Structural Insights on Pathogenic Effects, and Genotype-Phenotype Correlations |
spellingShingle |
SOS1 Mutations in Noonan Syndrome: Molecular Spectrum, Structural Insights on Pathogenic Effects, and Genotype-Phenotype Correlations Lepri, Francesca Noonan syndrome NS SOS1 mutation analysis structural analysis genotype-phenotype correlations |
title_short |
SOS1 Mutations in Noonan Syndrome: Molecular Spectrum, Structural Insights on Pathogenic Effects, and Genotype-Phenotype Correlations |
title_full |
SOS1 Mutations in Noonan Syndrome: Molecular Spectrum, Structural Insights on Pathogenic Effects, and Genotype-Phenotype Correlations |
title_fullStr |
SOS1 Mutations in Noonan Syndrome: Molecular Spectrum, Structural Insights on Pathogenic Effects, and Genotype-Phenotype Correlations |
title_full_unstemmed |
SOS1 Mutations in Noonan Syndrome: Molecular Spectrum, Structural Insights on Pathogenic Effects, and Genotype-Phenotype Correlations |
title_sort |
SOS1 Mutations in Noonan Syndrome: Molecular Spectrum, Structural Insights on Pathogenic Effects, and Genotype-Phenotype Correlations |
author |
Lepri, Francesca |
author_facet |
Lepri, Francesca De Luca, Alessandro Stella, Lorenzo Rossi, Cesare Baldassarre, Giuseppina Pantaleoni, Francesca Cordeddu, Viviana Williams, Bradley J. Dentici, Maria L. Caputo, Viviana Venanzi, Serenella Bonaguro, Michela Kavamura, Ines [UNIFESP] Faienza, Maria F. Pilotta, Alba Stanzial, Franco Faravelli, Francesca Gabrielli, Orazio Marino, Bruno Neri, Giovanni Silengo, Margherita Cirillo Ferrero, Giovanni B. Torrrente, Isabella Selicorni, Angelo Mazzanti, Laura Digilio, Maria C. Zampino, Giuseppe Dallapiccola, Bruno Gelb, Bruce D. Tartaglia, Marco |
author_role |
author |
author2 |
De Luca, Alessandro Stella, Lorenzo Rossi, Cesare Baldassarre, Giuseppina Pantaleoni, Francesca Cordeddu, Viviana Williams, Bradley J. Dentici, Maria L. Caputo, Viviana Venanzi, Serenella Bonaguro, Michela Kavamura, Ines [UNIFESP] Faienza, Maria F. Pilotta, Alba Stanzial, Franco Faravelli, Francesca Gabrielli, Orazio Marino, Bruno Neri, Giovanni Silengo, Margherita Cirillo Ferrero, Giovanni B. Torrrente, Isabella Selicorni, Angelo Mazzanti, Laura Digilio, Maria C. Zampino, Giuseppe Dallapiccola, Bruno Gelb, Bruce D. Tartaglia, Marco |
author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.institution.none.fl_str_mv |
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 Mt Sinai Sch Med |
dc.contributor.author.fl_str_mv |
Lepri, Francesca De Luca, Alessandro Stella, Lorenzo Rossi, Cesare Baldassarre, Giuseppina Pantaleoni, Francesca Cordeddu, Viviana Williams, Bradley J. Dentici, Maria L. Caputo, Viviana Venanzi, Serenella Bonaguro, Michela Kavamura, Ines [UNIFESP] Faienza, Maria F. Pilotta, Alba Stanzial, Franco Faravelli, Francesca Gabrielli, Orazio Marino, Bruno Neri, Giovanni Silengo, Margherita Cirillo Ferrero, Giovanni B. Torrrente, Isabella Selicorni, Angelo Mazzanti, Laura Digilio, Maria C. Zampino, Giuseppe Dallapiccola, Bruno Gelb, Bruce D. Tartaglia, Marco |
dc.subject.eng.fl_str_mv |
Noonan syndrome NS SOS1 mutation analysis structural analysis genotype-phenotype correlations |
topic |
Noonan syndrome NS SOS1 mutation analysis structural analysis genotype-phenotype correlations |
description |
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. |
publishDate |
2011 |
dc.date.issued.fl_str_mv |
2011-07-01 |
dc.date.accessioned.fl_str_mv |
2016-01-24T14:16:54Z |
dc.date.available.fl_str_mv |
2016-01-24T14:16:54Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
Human Mutation. Hoboken: Wiley-Blackwell, v. 32, n. 7, p. 760-772, 2011. |
dc.identifier.uri.fl_str_mv |
http://repositorio.unifesp.br/handle/11600/33809 http://dx.doi.org/10.1002/humu.21492 |
dc.identifier.issn.none.fl_str_mv |
1059-7794 |
dc.identifier.file.none.fl_str_mv |
WOS000292551800009.pdf |
dc.identifier.doi.none.fl_str_mv |
10.1002/humu.21492 |
dc.identifier.wos.none.fl_str_mv |
WOS:000292551800009 |
identifier_str_mv |
Human Mutation. Hoboken: Wiley-Blackwell, v. 32, n. 7, p. 760-772, 2011. 1059-7794 WOS000292551800009.pdf 10.1002/humu.21492 WOS:000292551800009 |
url |
http://repositorio.unifesp.br/handle/11600/33809 http://dx.doi.org/10.1002/humu.21492 |
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eng |
language |
eng |
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Human Mutation |
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http://olabout.wiley.com/WileyCDA/Section/id-406071.html |
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openAccess |
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760-772 |
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Wiley-Blackwell |
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Wiley-Blackwell |
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