SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations.

Giuseppe Zampino, Giovanni Neri, Marco Tartaglia, Francesca Lepri, Alessandro De Luca, Lorenzo Stella, Cesare Rossi, Giuseppina Baldassarre, Francesca Pantaleoni, Viviana Cordeddu, Bradley J. Williams, Maria L. Dentici, Viviana Caputo, Serenella Venanzi, Michela Bonaguro, Ines Kavamura, Maria F. Faienza, Alba Pilotta, Franco Stanzial, Francesca FaravelliOrazio Gabrielli, Bruno Marino, Margherita Cirillo Silengo, Giovanni B. Ferrero, Isabella Torrrente, Angelo Selicorni, Laura Mazzanti, Maria C. Digilio, Bruno Dallapiccola, Bruce D. Gelb

Risultato della ricerca: Contributo in rivistaArticolo in rivista

72 Citazioni (Scopus)

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 32:1-13, 2011. © 2011 Wiley-Liss, Inc
Lingua originaleEnglish
pagine (da-a)1-13
Numero di pagine13
RivistaHuman Mutation
Volume2011
Stato di pubblicazionePubblicato - 2011

Keywords

  • sos1

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