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Germline gain-of-function mutations in SOS1 cause Noonan syndrome.

Authors: Roberts, AE  Araki, T  Swanson, KD  Montgomery, KT  Schiripo, TA  Joshi, VA  Li, L  Yassin, Y  Tamburino, AM  Neel, BG  Kucherlapati, RS 
Citation: Roberts AE, etal., Nat Genet. 2007 Jan;39(1):70-4. Epub 2006 Dec 3.
Pubmed: (View Article at PubMed) PMID:17143285
DOI: Full-text: DOI:10.1038/ng1926

Noonan syndrome, the most common single-gene cause of congenital heart disease, is characterized by short stature, characteristic facies, learning problems and leukemia predisposition. Gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase SHP2, cause approximately 50% of Noonan syndrome cases. SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and Noonan syndrome mutants enhance ERK activation ex vivo and in mice. KRAS mutations account for <5% of cases of Noonan syndrome, but the gene(s) responsible for the remainder are unknown. We identified missense mutations in SOS1, which encodes an essential RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases of Noonan syndrome without PTPN11 mutation. The prevalence of specific cardiac defects differs in SOS1 mutation-associated Noonan syndrome. Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products that enhance RAS and ERK activation. Our results identify SOS1 mutants as a major cause of Noonan syndrome, representing the first example of activating GEF mutations associated with human disease and providing new insights into RAS-GEF regulation.

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CRRD Object Information
CRRD ID: 11063543
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.