Germline gain-of-function mutations in SOS1 cause Noonan syndrome - PubMed (original) (raw)
doi: 10.1038/ng1926. Epub 2006 Dec 3.
Affiliations
- PMID: 17143285
- DOI: 10.1038/ng1926
Germline gain-of-function mutations in SOS1 cause Noonan syndrome
Amy E Roberts et al. Nat Genet. 2007 Jan.
Abstract
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.
Comment in
- Sending out an SOS.
Shannon K, Bollag G. Shannon K, et al. Nat Genet. 2007 Jan;39(1):8-9. doi: 10.1038/ng0107-8. Nat Genet. 2007. PMID: 17192780 No abstract available.
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