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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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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