Abstract
Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies1. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome2,3,4,5,6. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome–associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.
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Change history
13 December 2006
In the version of this article initially published online, the labels ‘expression’ in Figure 2 panels a, b and d are incorrect. The correct labels are ‘activation’. In addition, author Giuseppe Zampino should have affiliation 8 rather than affiliation 7. These errors have been corrected for all version of the article.
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Acknowledgements
We are indebted to the individuals and families who participated in the study, the physicians who referred the subjects and the Joint Genome Institute Production Sequencing Group. We thank J. Kuriyan and H. Sondermann for helpful discussions. This work was supported by Telethon-Italy (grant GGP04172) and the 'Programma di Collaborazione Italia-USA/Malattie Rare' (M.T.); US National Institutes of Health grants HL71207, HD01294 and HL074728 (B.D.G.) and CA55360 and CA28146 (D.B.-S.) and Italian Ministry of Health Grant RC 2006 (B.D.). Research conducted at the E.O. Lawrence Berkeley National Laboratory and the Joint Genome Institute was performed under Department of Energy contract DE-AC0378SF00098 at the University of California (L.A.P.).
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Supplementary information
Supplementary Fig. 1
Facial dysmorphia in SOS1-associated Noonan syndrome. (PDF 288 kb)
Supplementary Table 1
Genotype-phenotype correlation (PDF 70 kb)
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Tartaglia, M., Pennacchio, L., Zhao, C. et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet 39, 75–79 (2007). https://doi.org/10.1038/ng1939
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DOI: https://doi.org/10.1038/ng1939
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