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Gain-of-function SOS1 mutations cause a distinctive form of noonan syndrome
- 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, Joes;
- Bristow, James;
- Carta, Claudio;
- Lepri, Francesca;
- Neri, Cinzia;
- Vasta, Isabella;
- Gibson, Kate;
- Curry, Cynthia J.;
- Lopez Siguero, Juan Pedro;
- Digilio, Maria Cristina;
- Zampino, Giuseppe;
- Dallapiccola, Bruno;
- Bar-Sagi, Dafna;
- Gelb, Brude D.
Abstract
Noonan syndrome (NS) is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies1. Increased RAS-mitogenactivated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations cause 50 percent of NS2-6. Here, we report that 22 of 129 NS patients without PTPN11 or KRAS mutation (17 percent) have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor (GEF). SOS1 mutations cluster at residues implicated in the maintenance of SOS1 in its autoinhibited form and ectopic expression of two NS-associated mutants induced enhanced RAS activation. The phenotype associated with SOS1 defects is distinctive, although within NS spectrum, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate for the first time gain-of-function mutations in a RAS GEF in inherited disease and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.
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