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Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome.

Authors: Tartaglia, M  Pennacchio, LA  Zhao, C  Yadav, KK  Fodale, V  Sarkozy, A  Pandit, B  Oishi, K  Martinelli, S  Schackwitz, W  Ustaszewska, A  Martin, J  Bristow, J  Carta, C  Lepri, F  Neri, C  Vasta, I  Gibson, K  Curry, CJ  Siguero, JP  Digilio, MC  Zampino, G  Dallapiccola, B  Bar-Sagi, D  Gelb, BD 
Citation: Tartaglia M, etal., Nat Genet. 2007 Jan;39(1):75-9. Epub 2006 Dec 13.
Pubmed: (View Article at PubMed) PMID:17143282
DOI: Full-text: DOI:10.1038/ng1939

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.

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CRRD Object Information
CRRD ID: 11063026
Created: 2016-04-27
Species: All species
Last Modified: 2016-04-27
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.