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Germline gain-of-function mutations in SOS1 cause Noonan syndrome

Nature Genetics volume 39, pages 7074 (2007) | Download Citation



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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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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Author notes

    • Amy E Roberts
    • , Toshiyuki Araki
    •  & Kenneth D Swanson

    These authors contributed equally to this work.


  1. Harvard Partners Center for Genetics and Genomics and Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Amy E Roberts
    • , Kate T Montgomery
    • , Taryn A Schiripo
    • , Victoria A Joshi
    • , Li Li
    • , Yosuf Yassin
    • , Alex M Tamburino
    •  & Raju S Kucherlapati
  2. Division of Genetics, Department of Medicine, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Amy E Roberts
  3. Cancer Biology Program, Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Toshiyuki Araki
    • , Kenneth D Swanson
    •  & Benjamin G Neel
  4. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Victoria A Joshi


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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Benjamin G Neel.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Noonan syndrome–associated SOS1 mutants cause sustained ERK activation.

  2. 2.

    Supplementary Fig. 2

    Noonan syndrome–associated SOS1 mutants enhance endogenous ERK activation.

  3. 3.

    Supplementary Table 1

    Genotype-phenotype correlations in Noonan syndrome

  4. 4.

    Supplementary Table 2

    Primer pairs used for gene amplification.

  5. 5.

    Supplementary Methods

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