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.
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References
Tartaglia, M. & Gelb, B.D. Noonan syndrome and related disorders: genetics and pathogenesis. Annu. Rev. Genomics Hum. Genet. 6, 45–68 (2005).
Tartaglia, M. et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat. Genet. 29, 465–468 (2001).
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).
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).
Vetter, I.R. & Wittinghofer, A. The guanine nucleotide-binding switch in three dimensions. Science 294, 1299–1304 (2001).
Donovan, S., Shannon, K.M. & Bollag, G. GTPase activating proteins: critical regulators of intracellular signaling. Biochim. Biophys. Acta 1602, 23–45 (2002).
Bos, J.L. ras oncogenes in human cancer: a review. Cancer Res. 49, 4682–4689 (1989).
Lauchle, J.O., Braun, B.S., Loh, M.L. & Shannon, K. Inherited predispositions and hyperactive Ras in myeloid leukemogenesis. Pediatr. Blood Cancer (2005).
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).
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).
Tartaglia, M. et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat. Genet. 34, 148–150 (2003).
Kratz, C.P. et al. The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood 106, 2183–2185 (2005).
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).
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).
Chan, R.J. et al. Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor. Blood 105, 3737–3742 (2005).
Schubbert, S. et al. Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells. Blood 106, 311–317 (2005).
Bollag, G. et al. Biochemical characterization of a novel KRAS insertional mutation from a human leukemia. J. Biol. Chem. 273, 32491–32494 (1996).
Bollag, G. & McCormick, F. Differential regulation of rasGAP and neurofibromatosis gene product activities. Nature 351, 576–579 (1991).
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).
Aoki, Y. et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat. Genet. 37, 1038–1040 (2005).
Tuveson, D.A. et al. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375–387 (2004).
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).
Marshall, C. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179–185 (1995).
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).
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).
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).
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).
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).
Zenker, M. et al. Genotype-phenotype correlations in Noonan syndrome. J. Pediatr. 144, 368–374 (2004).
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).
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.
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H.N., B.W., G.B. and K.Y.J.Z.are employees of Plexxikon.
Supplementary information
Supplementary Fig. 1
Sequence alignments of two regions of human K-Ras isoforms with their orthologs in different species. (PDF 99 kb)
Supplementary Fig. 2
Locations of Val14 and Thr58 in the Ras/p120 GAP co-crystal structure. (PDF 1310 kb)
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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
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DOI: https://doi.org/10.1038/ng1748
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