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

TitleActivating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome.
Publication TypeJournal Article
Year of Publication2015
AuthorsCordeddu, V, Yin, JC, Gunnarsson, C, Virtanen, C, Drunat, S, Lepri, F, De Luca, A, Rossi, C, Ciolfi, A, Pugh, TJ, Bruselles, A, Priest, JR, Pennacchio, LA, Lu, Z, Danesh, A, Quevedo, R, Hamid, A, Martinelli, S, Pantaleoni, F, Gnazzo, M, Daniele, P, Lissewski, C, Bocchinfuso, G, Stella, L, Odent, S, Philip, N, Faivre, L, Vlckova, M, Seemanova, E, Digilio, C, Zenker, M, Zampino, G, Verloes, A, Dallapiccola, B, Roberts, AE, Cavé, H, Gelb, BD, Neel, BG, Tartaglia, M
JournalHum Mutat
Date Published2015 Nov
KeywordsAdolescent, Adult, Alleles, Amino Acid Substitution, Child, DNA Mutational Analysis, Exome, Facies, Female, Genetic Association Studies, Genotype, Humans, Male, Models, Molecular, Mutation, Noonan Syndrome, Phenotype, Protein Conformation, Protein Interaction Domains and Motifs, Son of Sevenless Proteins, Young Adult

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.

Alternate JournalHum. Mutat.
PubMed ID26173643
PubMed Central IDPMC4604019
Grant ListR01 HG003988 / HG / NHGRI NIH HHS / United States
P30 CA016087 / CA / NCI NIH HHS / United States
R01 HL0832732 / HL / NHLBI NIH HHS / United States
U01 DE020060 / DE / NIDCR NIH HHS / United States
R01 HL083273 / HL / NHLBI NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
K12 HD000850 / HD / NICHD NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
R01 HL071207 / HL / NHLBI NIH HHS / United States
GGP13107 / / Telethon / Italy
U54 HG006997 / HG / NHGRI NIH HHS / United States