Letter abstract
Nature Genetics 39, 70 - 74 (2006)
Published online: 3 December 2006 | doi:10.1038/ng1926
Germline gain-of-function mutations in SOS1 cause Noonan syndrome
Amy E Roberts1,2,5, Toshiyuki Araki3,5, Kenneth D Swanson3,5, Kate T Montgomery1, Taryn A Schiripo1, Victoria A Joshi1,4, Li Li1, Yosuf Yassin1, Alex M Tamburino1, Benjamin G Neel3 & Raju S Kucherlapati1
Noonan syndrome, the most common single-gene cause of congenital heart disease, is characterized by short stature, characteristic facies, learning problems and leukemia predisposition1. Gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase SHP2, cause 
50% of Noonan syndrome cases. SHP2 is required for RAS-ERKMAP kinase (MAPK) cascade activation2, and Noonan syndrome mutants enhance ERK activation ex vivo3, 4 and in mice5. KRAS mutations account for <5% of cases of Noonan syndrome6, 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 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.
- Harvard Partners Center for Genetics and Genomics and Harvard Medical School, Boston, Massachusetts 02115, USA.
- Division of Genetics, Department of Medicine, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA.
- Cancer Biology Program, Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
- These authors contributed equally to this work.
Correspondence to: Benjamin G Neel3 e-mail: bneel@bidmc.harvard.edu
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