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SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype–phenotype correlations
Author(s) -
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,
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
Publication year - 2011
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21492
Subject(s) - biology , noonan syndrome , missense mutation , genetics , phenotype , mutation , genotype , mendelian inheritance , genetic heterogeneity , costello syndrome , gene , kras
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. © 2011 Wiley‐Liss, Inc.