Abstract
Noonan syndrome (MIM 163950) is an autosomal dominant disorder characterized by dysmorphic facial features, proportionate short stature and heart disease (most commonly pulmonic stenosis and hypertrophic cardiomyopathy)1,2. Webbed neck, chest deformity, cryptorchidism, mental retardation and bleeding diatheses also are frequently associated with this disease. This syndrome is relatively common, with an estimated incidence of 1 in 1,000–2,500 live births. It has been mapped to a 5-cM region (N-SH2) on chromosome 12q24.1, and genetic heterogeneity has also been documented3,4,5,6. Here we show that missense mutations in PTPN11 (MIM 176876)—a gene encoding the nonreceptor protein tyrosine phosphatase SHP-2, which contains two Src homology 2 (SH2) domains—cause Noonan syndrome and account for more than 50% of the cases that we examined. All PTPN11 missense mutations cluster in interacting portions of the amino N-SH2 domain and the phosphotyrosine phosphatase domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of two N-SH2 mutants indicates that in these mutants there may be a significant shift of the equilibrium favoring the active conformation. This implies that they are gain-of-function changes and that the pathogenesis of Noonan syndrome arises from excessive SHP-2 activity.
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
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Noonan, J.A. Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease. Am. J. Dis. Child. 116, 373–380 (1968).
Allanson, J.E. Noonan syndrome. J. Med. Genet. 24, 9–13 (1987).
Jamieson, C.R. et al. Mapping a gene for Noonan syndrome to the long arm of chromosome 12. Nature Genet. 8, 357–360 (1994).
Brady, A.F. et al. Further delineation of the critical region for Noonan syndrome on the long arm of chromosome 12. Eur. J. Hum. Genet. 5, 336–337 (1997).
Legius, E., Schollen, E., Matthijs, G. & Fryns, J.P. Fine mapping of Noonan/cardio-facio cutaneous syndrome in a large family. Eur. J. Hum. Genet. 6, 32–37 (1998).
van Der Burgt, I. & Brunner, H. Genetic heterogeneity in Noonan syndrome: evidence for an autosomal recessive form. Am. J. Med. Genet. 94, 46–51 (2000).
Dechert, U. et al. Protein-tyrosine phosphatase SH-PTP2 (PTPN11) is localized to 12q24.1-24.3. Hum. Genet. 96, 609–615 (1995).
Feng, G.-S. Shp-2 tyrosine phosphatase: signaling one cell or many. Exp. Cell Res. 253, 47–54 (1999).
Chen, B. et al. Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis. Nature Genet. 24, 296–299 (2000).
Lee, C.H. et al. Crystal structures of peptide complexes of the amino-terminal SH2 domain of the Syp tyrosine phosphatase. Structure 2, 423–438 (1994).
Eck, M.J., Pluskey, S., Trub, T., Harrison, S.C. & Shoelson, S.E. Spatial constraints on the recognition of phosphoproteins by the tandem SH2 domains of the phosphatase SH-PTP2. Nature 379, 277–280 (1996).
Hof, P., Pluskey, S., Dhe-Paganon, S., Eck, M.J. & Shoelson, S.E. Crystal structure of the tyrosine phosphatase SHP-2. Cell 92, 441–450 (1998).
Allen, M.P. & Tildesley . Computer Simulation of Liquids (Clarendon, Oxford, 1987).
Noguti, T. & Go, N. Efficient Monte Carlo method for simulation of fluctuating conformations of native proteins. Biopolymers 24, 527–546 (1985).
O'Reilly, A.M., Pluskey, S., Shoelson, S.E. & Neel, B.G. Activated mutants of SHP-2 preferentially induce elongation of Xenopus animal caps. Mol. Cell. Biol. 20, 299–311 (2000).
Arrandale, J.M. et al. Insulin signaling in mice expressing reduced levels of Syp. J. Biol. Chem. 271, 21353–21358 (1996).
Saxton, T.M. et al. Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase Shp-2. EMBO J. 16, 2352–2364 (1997).
Tang, T.L., Freeman, R.M. Jr, O'Reilly, A.M., Neel, B.G. & Sokol, S.Y. The SH2-containing protein-tyrosine phosphatase SH-PTP2 is required upstream of MAP kinase for early Xenopus development. Cell 80, 473–483 (1995).
Perkins, L.A., Johnson, M.R., Melnick, M.B. & Perrimon, N. The nonreceptor protein tyrosine phosphatase corkscrew functions in multiple receptor tyrosine kinase pathways in Drosophila. Dev. Biol. 180, 63–81 (1996).
Qu, C.K. et al. Biased suppression of hematopoiesis and multiple developmental defects in chimeric mice containing Shp-2 mutant cells. Mol. Cell. Biol. 18, 6075–6082 (1998).
Saxton, T.M. et al. The SH2 tyrosine phosphatase shp2 is required for mammalian limb development. Nature Genet. 24, 420–423 (2000).
Stein-Gerlach, M., Wallasch, C. & Ullrich, A. SHP-2, SH2-containing protein tyrosine phosphatase-2. Int. J. Biochem. Cell. Biol. 30, 559–566 (1998).
Tamir, I., Dal Porto, J.M. & Cambier, J.C. Cytoplasmic protein tyrosine phosphatase SHP-1 and SHP-2: regulators of B cell signal transduction. Curr. Opin. Immunol. 12, 307–315 (2000).
Shi, Z.Q., Lu, W. & Feng, G.S. The Shp-2 tyrosine phosphatase has opposite effects in mediating the activation of extracellular signal-regulated and c-Jun NH2-terminal mitogen-activated protein kinases. J. Biol. Chem. 273, 4904–4908 (1998).
You, M., Yu, D.H. & Feng, G.S. Shp-2 tyrosine phosphatase functions as a negative regulator of the interferon-stimulated Jak/STAT pathway. Mol. Cell. Biol. 19, 2416–2424 (1999).
Maroun, C.R., Naujokas, M.A., Holgado-Madruga, M., Wong, A.J. & Park, M. The tyrosine phosphatase SHP-2 is required for sustained activation of extracellular signal-regulated kinase and epithelial morphogenesis downstream from the met receptor tyrosine kinase. Mol. Cell. Biol. 20, 8513–8525 (2000).
You, M., Flick, L.M., Yu, D. & Feng, G.S. Modulation of the nuclear factor κB pathway by Shp-2 tyrosine phosphatase in mediating the induction of interleukin (IL)-6 by IL-1 or tumor necrosis factor. J. Exp. Med. 193, 101–110 (2001).
Brooks, B.R. et al. CHARMM — a program for macromolecular energy, minimization and dynamics calculations. J. Comput. Chem. 4, 165–175 (1983).
MacKerell, A.D. et al. All-atom empirical potential for molecular modeling and dynamics studies of proteins. J. Phys. Chem. B 102, 3586–3616 (1998).
Hassan, S.A., Mehler, E.L. & Weinstein, H. in Lecture Notes Series in Computational Science (ed. Schlick, T.) (Springer, New York, in press).
Shenkin, P.S. & McDonald, D.Q. Cluster analysis of molecular conformations. J. Comput. Chem. 15, 899–916 (1994).
Hassan, S.A., Guarnieri, F. & Mehler, E.L. A general treatment of solvent effects based on screened Coulomb potentials. J. Phys. Chem. B 104, 6478–6489 (2000).
Acknowledgements
We thank the individuals with Noonan syndrome and their families who participated in this study, the physicians who referred the subjects, X. Song for technical assistance, H. Weinstein for insightful suggestions about the structural analysis, S. Hassan for providing algorithms and programs to carry out the Montre Carlo calculations and for discussions and G. Diaz and Y. Ioannou for reading the manuscript. This work was supported in part by grants from the NIH (to B.D.G., E.L.M. and R.K.) and from the Human Genetics Program at the Albert Einstein College of Medicine (to R.K.).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Tartaglia, M., Mehler, E., Goldberg, R. et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 29, 465–468 (2001). https://doi.org/10.1038/ng772
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng772
This article is cited by
-
Assessment of the FRET-based Teen sensor to monitor ERK activation changes preceding morphological defects in a RASopathy zebrafish model and phenotypic rescue by MEK inhibitor
Molecular Medicine (2024)
-
Genetics of SLE: mechanistic insights from monogenic disease and disease-associated variants
Nature Reviews Nephrology (2023)
-
Neurosurgical aspects of Noonan syndrome
Child's Nervous System (2023)
-
PTPN11 variant may be a prognostic indicator of IDH-wildtype glioblastoma in a comprehensive genomic profiling cohort
Journal of Neuro-Oncology (2023)
-
Refractory thrombocytopenia could be a rare initial presentation of Noonan syndrome in newborn infants: a case report and literature review
BMC Pediatrics (2022)