SOS1 Mutations in Noonan Syndrome: Molecular Spectrum, Structural Insights on Pathogenic Effects, and Genotype-Phenotype Correlations

SOS1 Mutations in Noonan Syndrome: Molecular Spectrum, Structural Insights on Pathogenic Effects, and Genotype-Phenotype Correlations

Author Lepri, Francesca Google Scholar
De Luca, Alessandro Google Scholar
Stella, Lorenzo Google Scholar
Rossi, Cesare Google Scholar
Baldassarre, Giuseppina Google Scholar
Pantaleoni, Francesca Google Scholar
Cordeddu, Viviana Google Scholar
Williams, Bradley J. Google Scholar
Dentici, Maria L. Google Scholar
Caputo, Viviana Google Scholar
Venanzi, Serenella Google Scholar
Bonaguro, Michela Google Scholar
Kavamura, Ines Autor UNIFESP Google Scholar
Faienza, Maria F. Google Scholar
Pilotta, Alba Google Scholar
Stanzial, Franco Google Scholar
Faravelli, Francesca Google Scholar
Gabrielli, Orazio Google Scholar
Marino, Bruno Google Scholar
Neri, Giovanni Google Scholar
Silengo, Margherita Cirillo Google Scholar
Ferrero, Giovanni B. Google Scholar
Torrrente, Isabella Google Scholar
Selicorni, Angelo Google Scholar
Mazzanti, Laura Google Scholar
Digilio, Maria C. Google Scholar
Zampino, Giuseppe Google Scholar
Dallapiccola, Bruno Google Scholar
Gelb, Bruce D. Google Scholar
Tartaglia, Marco Google Scholar
Institution 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
Abstract 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.
Keywords Noonan syndrome
NS
SOS1
mutation analysis
structural analysis
genotype-phenotype correlations
Language English
Sponsor 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
Grant number 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
Date 2011-07-01
Published in Human Mutation. Hoboken: Wiley-Blackwell, v. 32, n. 7, p. 760-772, 2011.
ISSN 1059-7794 (Sherpa/Romeo, impact factor)
Publisher Wiley-Blackwell
Extent 760-772
Origin http://dx.doi.org/10.1002/humu.21492
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000292551800009
URI http://repositorio.unifesp.br/handle/11600/33809

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