Abstract
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-ERK MAP 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.
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Acknowledgements
We are indebted to the dedicated patients and families with Noonan syndrome who volunteered for this research study, W. Robinson (Noonan Syndrome Support Group) and the referring physicians. This work was supported in part by US National Institutes of Health grants DE16140 (to R.S.K.), R37CA49152 (to B.G.N.) and MO1-RR02172; the National Center for Research Resources, Children's Hospital Boston General Clinical Research Center and the Harvard Partners Center for Genetics and Genomics (A.E.R.). T. A. is a Special Fellow of the Leukemia and Lymphoma Society.
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The study was designed by A.E.R., R.S.K, and B.G.N., patient phenotyping was performed by A.E.R. and T.A.S.; gene sequencing was conducted by K.T.M., V.A.J., L.L., Y.Y. and A.M.T. and structural and biochemical analysis by K.D.S., T.A. and B.G.N.
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Supplementary information
Supplementary Fig. 1
Noonan syndrome–associated SOS1 mutants cause sustained ERK activation. (PDF 83 kb)
Supplementary Fig. 2
Noonan syndrome–associated SOS1 mutants enhance endogenous ERK activation. (PDF 98 kb)
Supplementary Table 1
Genotype-phenotype correlations in Noonan syndrome (PDF 158 kb)
Supplementary Table 2
Primer pairs used for gene amplification. (PDF 119 kb)
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Roberts, A., Araki, T., Swanson, K. et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet 39, 70–74 (2007). https://doi.org/10.1038/ng1926
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DOI: https://doi.org/10.1038/ng1926
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