z-logo
Premium
Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome
Author(s) -
Cordeddu Viviana,
Yin Jiani C.,
Gunnarsson Cecilia,
Virtanen Carl,
Drunat Séverine,
Lepri Francesca,
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
Publication year - 2015
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.22834
Subject(s) - biology , missense mutation , noonan syndrome , costello syndrome , guanine nucleotide exchange factor , genetics , signal transduction , mutation , ptpn11 , phenotype , gene , cancer research , kras
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.

This content is not available in your region!

Continue researching here.

Having issues? You can contact us here