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Nat Genet. 2007 Jan;39(1):8-9.
Germline gain-of-function mutations in SOS1 cause Noonan syndrome.
Roberts AE,
Araki T,
Swanson KD,
Montgomery KT,
Schiripo TA,
Joshi VA,
Li L,
Yassin Y,
Tamburino AM,
Neel BG,
Kucherlapati RS.
Harvard Partners Center for Genetics and Genomics and Harvard Medical School, Boston, Massachusetts 02115, USA.
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.
PMID: 17143285 [PubMed - indexed for MEDLINE]