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

• Published in: Human mutation Vol. 36; no. 11; pp. 1080 - 1087
• Main Authors: Cordeddu, Viviana, Yin, Jiani C., Gunnarsson, Cecilia, Virtanen, Carl, Drunat, Séverine, Lepri, Francesca, De Luca, Alessandro, Rossi, Cesare, Ciolfi, Andrea, Pugh, Trevor J., Bruselles, Alessandro, Priest, James R., Pennacchio, Len A., Lu, Zhibin, Danesh, Arnavaz, Quevedo, Rene, Hamid, Alaa, Martinelli, Simone, Pantaleoni, Francesca, Gnazzo, Maria, Daniele, Paola, Lissewski, Christina, Bocchinfuso, Gianfranco, Stella, Lorenzo, Odent, Sylvie, Philip, Nicole, Faivre, Laurence, Vlckova, Marketa, Seemanova, Eva, Digilio, Cristina, Zenker, Martin, Zampino, Giuseppe, Verloes, Alain, Dallapiccola, Bruno, Roberts, Amy E., Cavé, Hélène, Gelb, Bruce D., Neel, Benjamin G., Tartaglia, Marco
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.11.2015; Hindawi Limited; Wiley
• Subjects: Adolescent; Adult; Alleles; Amino Acid Substitution; Child; DNA Mutational Analysis; Drosophila; Exome; Facies; Female; Genetic Association Studies; Genetic disorders; Genotype; genotype-phenotype correlations; Humans; Life Sciences; Male; Models, Molecular; Mutation; Noonan syndrome; Noonan Syndrome - diagnosis; Noonan Syndrome - genetics; Phenotype; Protein Conformation; Protein Interaction Domains and Motifs - genetics; RAS signaling; Signal transduction; Son of Sevenless Proteins - chemistry; Son of Sevenless Proteins - genetics; SOS2; Young Adult; genotype-phenotype correlations; SOS2; Noonan syndrome; RAS signaling
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.22834

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. Noonan syndrome‐causing mutations alter the Dbl homology domain (DH, shown as ribbon), altering its interaction with the RAS exchange motif, colored by its electrostatic potential. The mutated residue in the DH domain are colored red.