Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome

Giuseppe Zampino, Viviana Cordeddu, Jiani C. Yin, Cecilia Gunnarsson, Carl Virtanen, Séverine Drunat, Francesca Lepri, Alessandro De Luca, Cesare Rossi, Andrea Ciolfi, Trevor J. Pugh, Alessandro Bruselles, James R. Priest, Len A. Pennacchio, Zhibin Lu, Arnavaz Danesh, Rene Quevedo, Alaa Hamid, Simone Martinelli, Francesca PantaleoniMaria Gnazzo, Paola Daniele, Christina Lissewski, Gianfranco Bocchinfuso, Lorenzo Stella, Sylvie Odent, Nicole Philip, Laurence Faivre, Marketa Vlckova, Eva Seemanova, Cristina Digilio, Martin Zenker, Alain Verloes, Bruno Dallapiccola, Amy E. Roberts, Hélène Cavé, Bruce D. Gelb, Benjamin G. Neel, Marco Tartaglia

Risultato della ricerca: Contributo in rivistaArticolo in rivista

44 Citazioni (Scopus)

Abstract

The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals. Here, we report that missense mutations altering Son of Sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology (DH) domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its autoinhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the DH domain.
Lingua originaleEnglish
pagine (da-a)1080-1087
Numero di pagine8
RivistaHuman Mutation
Volume36
DOI
Stato di pubblicazionePubblicato - 2015

Keywords

  • Adolescent
  • Adult
  • Alleles
  • Amino Acid Substitution
  • Child
  • DNA Mutational Analysis
  • Exome
  • Facies
  • Female
  • Genetic Association Studies
  • Genotype
  • Genotype-phenotype correlations
  • Humans
  • Male
  • Models, Molecular
  • Mutation
  • Noonan Syndrome
  • Noonan syndrome
  • Phenotype
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • RAS signaling
  • SOS2
  • Son of Sevenless Proteins
  • Young Adult

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