Germline KRAS mutations cause Noonan syndrome (original) (raw)

Nature Genetics volume 38, pages 331–336 (2006)Cite this article

A Corrigendum to this article was published on 01 May 2006

Abstract

Noonan syndrome (MIM 163950) is characterized by short stature, facial dysmorphism and cardiac defects1. Heterozygous mutations in PTPN11, which encodes SHP-2, cause ∼50% of cases of Noonan syndrome1,2. The SHP-2 phosphatase relays signals from activated receptor complexes to downstream effectors, including Ras3. We discovered de novo germline KRAS mutations that introduce V14I, T58I or D153V amino acid substitutions in five individuals with Noonan syndrome and a P34R alteration in a individual with cardio-facio-cutaneous syndrome (MIM 115150), which has overlapping features with Noonan syndrome1,4. Recombinant V14I and T58I K-Ras proteins show defective intrinsic GTP hydrolysis and impaired responsiveness to GTPase activating proteins, render primary hematopoietic progenitors hypersensitive to growth factors and deregulate signal transduction in a cell lineage–specific manner. These studies establish germline KRAS mutations as a cause of human disease and infer that the constellation of developmental abnormalities seen in Noonan syndrome spectrum is, in large part, due to hyperactive Ras.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Tartaglia, M. & Gelb, B.D. Noonan syndrome and related disorders: genetics and pathogenesis. Annu. Rev. Genomics Hum. Genet. 6, 45–68 (2005).
    Article CAS Google Scholar
  2. Tartaglia, M. et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat. Genet. 29, 465–468 (2001).
    Article CAS Google Scholar
  3. Neel, B.G., Gu, H. & Pao, L. The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem. Sci. 28, 284–293 (2003).
    Article CAS Google Scholar
  4. Kavamura, M.I., Peres, C.A., Alchorne, M.M. & Brunoni, D. CFC index for the diagnosis of cardiofaciocutaneous syndrome. Am. J. Med. Genet. 112, 12–16 (2002).
    Article CAS Google Scholar
  5. Vetter, I.R. & Wittinghofer, A. The guanine nucleotide-binding switch in three dimensions. Science 294, 1299–1304 (2001).
    Article CAS Google Scholar
  6. Donovan, S., Shannon, K.M. & Bollag, G. GTPase activating proteins: critical regulators of intracellular signaling. Biochim. Biophys. Acta 1602, 23–45 (2002).
    CAS PubMed Google Scholar
  7. Bos, J.L. ras oncogenes in human cancer: a review. Cancer Res. 49, 4682–4689 (1989).
    CAS PubMed Google Scholar
  8. Lauchle, J.O., Braun, B.S., Loh, M.L. & Shannon, K. Inherited predispositions and hyperactive Ras in myeloid leukemogenesis. Pediatr. Blood Cancer (2005).
  9. Bollag, G. et al. Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in murine and human hematopoietic cells. Nat. Genet. 12, 144–148 (1996).
    Article CAS Google Scholar
  10. Side, L. et al. Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders. N. Engl. J. Med. 336, 1713–1720 (1997).
    Article CAS Google Scholar
  11. Tartaglia, M. et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat. Genet. 34, 148–150 (2003).
    Article CAS Google Scholar
  12. Kratz, C.P. et al. The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood 106, 2183–2185 (2005).
    Article CAS Google Scholar
  13. Keilhack, H., David, F.S., McGregor, M., Cantley, L.C. & Neel, B.G. Diverse biochemical properties of Shp2 mutants: Implications for disease phenotypes. J. Biol. Chem. 280, 30984–30993 (2005).
    Article CAS Google Scholar
  14. Mohi, M.G. et al. Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations. Cancer Cell 7, 179–191 (2005).
    Article CAS Google Scholar
  15. Chan, R.J. et al. Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor. Blood 105, 3737–3742 (2005).
    Article CAS Google Scholar
  16. Schubbert, S. et al. Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells. Blood 106, 311–317 (2005).
    Article CAS Google Scholar
  17. Bollag, G. et al. Biochemical characterization of a novel KRAS insertional mutation from a human leukemia. J. Biol. Chem. 273, 32491–32494 (1996).
    Article Google Scholar
  18. Bollag, G. & McCormick, F. Differential regulation of _ras_GAP and neurofibromatosis gene product activities. Nature 351, 576–579 (1991).
    Article CAS Google Scholar
  19. Serrano, M., Lin, A.W., McCurrach, M.E., Beach, D. & Lowe, S.W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997).
    Article CAS Google Scholar
  20. Aoki, Y. et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat. Genet. 37, 1038–1040 (2005).
    Article CAS Google Scholar
  21. Tuveson, D.A. et al. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375–387 (2004).
    Article CAS Google Scholar
  22. Johnson, L. et al. K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes Dev. 11, 2468–2481 (1997).
    Article CAS Google Scholar
  23. Marshall, C. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179–185 (1995).
    Article CAS Google Scholar
  24. Franken, S.M. et al. Three-dimensional structures and properties of a transforming and a nontransforming glycine-12 mutant of p21H-ras. Biochemistry 32, 8411–8420 (1993).
    Article CAS Google Scholar
  25. Largaespada, D.A., Brannan, C.I., Jenkins, N.A. & Copeland, N.G. Nf1 deficiency causes Ras-mediated granulocyte-macrophage colony stimulating factor hypersensitivity and chronic myeloid leukemia. Nat. Genet. 12, 137–143 (1996).
    Article CAS Google Scholar
  26. Hiatt, K.K., Ingram, D.A., Zhang, Y., Bollag, G. & Clapp, D.W. Neurofibromin GTPase-activating protein-related domains restore normal growth in Nf1−/− cells. J. Biol. Chem. 276, 7240–7245 (2001).
    Article CAS Google Scholar
  27. Stone, J.C., Colleton, M. & Bottorff, D. Effector domain mutations dissociate p21ras effector function and GTPase-activating protein interaction. Mol. Cell. Biol. 13, 7311–7320 (1993).
    Article CAS Google Scholar
  28. Araki, T. et al. Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation. Nat. Med. 10, 849–857 (2004).
    Article CAS Google Scholar
  29. Zenker, M. et al. Genotype-phenotype correlations in Noonan syndrome. J. Pediatr. 144, 368–374 (2004).
    Article CAS Google Scholar
  30. Donovan, S., See, W., Bonifas, J., Stokoe, D. & Shannon, K.M. Hyperactivation of protein kinase B and ERK have discrete effects on survival, proliferation, and cytokine expression in Nf1-deficient myeloid cells. Cancer Cell 2, 507–514 (2002).
    Article CAS Google Scholar

Download references

Acknowledgements

We are indebted to A. Struwe, Karolinen-Hospital Hüsten, G. Gillessen-Kaesbach and D. Wieczorek, Institute of Human Genetics Essen; P. Meinecke, Altona Children's Hospital, Hamburg and A. Tzschach, Max Planck Institute of Molecular Genetics, Berlin for providing DNA and clinical information for individuals included in this study. We also thank A. Diem for excellent technical assistance and R. Hawley for providing the MSCV vector. We acknowledge S. McQuiston and S. Elmes of the Laboratory for Cell Analysis Shared resource of the UCSF Comprehensive Cancer Center for assistance with cell sorting. This work was supported, in part, by US National Institutes of Health grants R01 CA72614 and R01 CA104282 and by the Deutsche José Carreras Leukämie-Stiftung e.V (DJCLS R02/10 JMML/MDS). We are grateful to R. Chan, F. McCormick, D. Tuveson and R. Van Etten for technical advice and critical comments. We apologize to investigators whose work we did not cite due to the limited number of references permitted.

Author information

Authors and Affiliations

  1. Department of Pediatrics, University of California, 513 Parnassus Avenue, San Francisco, 94143, California, USA
    Suzanne Schubbert, Sara L Rowe & Kevin Shannon
  2. Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, 91054, Germany
    Martin Zenker & Anita Rauch
  3. Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Mathildenstrasse 1, Freiburg, 79106, Germany
    Silke Böll, Cornelia Klein, Charlotte M Niemeyer & Christian P Kratz
  4. Plexxikon, Inc., 91 Bolivar Dr., Berkeley, 94710, California, USA
    Gideon Bollag, Hoa Nguyen, Brian West & Kam Y J Zhang
  5. Department of Human Genetics, University Medical Center Nijmegen, Nijmegen, 6500 HB, The Netherlands
    Ineke van der Burgt & Erik Sistermans
  6. Max Planck Institute of Molecular Genetics, Berlin, 14195, Germany
    Luciana Musante & Vera Kalscheuer
  7. Institute of Human Genetics, University of Göttingen, 37075, Germany
    Lars-Erik Wehner
  8. Comprehensive Cancer Center, University of California, San Francisco, 94115, California, USA
    Kevin Shannon

Authors

  1. Suzanne Schubbert
    You can also search for this author inPubMed Google Scholar
  2. Martin Zenker
    You can also search for this author inPubMed Google Scholar
  3. Sara L Rowe
    You can also search for this author inPubMed Google Scholar
  4. Silke Böll
    You can also search for this author inPubMed Google Scholar
  5. Cornelia Klein
    You can also search for this author inPubMed Google Scholar
  6. Gideon Bollag
    You can also search for this author inPubMed Google Scholar
  7. Ineke van der Burgt
    You can also search for this author inPubMed Google Scholar
  8. Luciana Musante
    You can also search for this author inPubMed Google Scholar
  9. Vera Kalscheuer
    You can also search for this author inPubMed Google Scholar
  10. Lars-Erik Wehner
    You can also search for this author inPubMed Google Scholar
  11. Hoa Nguyen
    You can also search for this author inPubMed Google Scholar
  12. Brian West
    You can also search for this author inPubMed Google Scholar
  13. Kam Y J Zhang
    You can also search for this author inPubMed Google Scholar
  14. Erik Sistermans
    You can also search for this author inPubMed Google Scholar
  15. Anita Rauch
    You can also search for this author inPubMed Google Scholar
  16. Charlotte M Niemeyer
    You can also search for this author inPubMed Google Scholar
  17. Kevin Shannon
    You can also search for this author inPubMed Google Scholar
  18. Christian P Kratz
    You can also search for this author inPubMed Google Scholar

Corresponding authors

Correspondence toKevin Shannon or Christian P Kratz.

Ethics declarations

Competing interests

H.N., B.W., G.B. and K.Y.J.Z.are employees of Plexxikon.

Supplementary information

Rights and permissions

About this article

Cite this article

Schubbert, S., Zenker, M., Rowe, S. et al. Germline KRAS mutations cause Noonan syndrome.Nat Genet 38, 331–336 (2006). https://doi.org/10.1038/ng1748

Download citation

This article is cited by