Please use this identifier to cite or link to this item: https://repositorio.unifesp.br/handle/11600/33809
Title: SOS1 Mutations in Noonan Syndrome: Molecular Spectrum, Structural Insights on Pathogenic Effects, and Genotype-Phenotype Correlations
Authors: 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
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
Keywords: Noonan syndrome
NS
SOS1
mutation analysis
structural analysis
genotype-phenotype correlations
Issue Date: 1-Jul-2011
Publisher: Wiley-Blackwell
Citation: Human Mutation. Hoboken: Wiley-Blackwell, v. 32, n. 7, p. 760-772, 2011.
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.
URI: http://repositorio.unifesp.br/handle/11600/33809
ISSN: 1059-7794
Other Identifiers: http://dx.doi.org/10.1002/humu.21492
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