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- Title
Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome.
- Authors
Tartaglia, Marco; Pennacchio, Len A; Zhao, Chen; Yadav, Kamlesh K; Fodale, Valentina; Sarkozy, Anna; Pandit, Bhaswati; Oishi, Kimihiko; Martinelli, Simone; Schackwitz, Wendy; Ustaszewska, Anna; Martin, Joel; Bristow, James; Carta, Claudio; Lepri, Francesca; Neri, Cinzia; Vasta, Isabella; Gibson, Kate; Curry, Cynthia J; Siguero, Juan Pedro López; Digilio, Maria Cristina; Zampino, Giuseppe; Dallapiccola, Bruno; Bar-Sagi, Dafna; Gelb, Bruce D
- Abstract
Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome-associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.
- Publication
Nature genetics, 2007, Vol 39, Issue 1, p75
- ISSN
1061-4036
- Publication type
Journal Article
- DOI
10.1038/ng1939