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Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome

Nature Genetics volume 29, pages 465–468 (2001)Cite this article

An Erratum to this article was published on 01 January 2002

A Correction to this article was published on 01 December 2001

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.

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Figure 1: PTPN11 organization and SHP-2 domain structure.
Figure 2: PTPN11 mutations in Noonan syndrome.
Figure 3: Structure of SHP-2 with mutated residues.
Figure 4: Plots of root mean-square deviation (RMSD) against energy for the wildtype and two mutant N-SH2 segments of SHP-2.

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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.).

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Authors and Affiliations

  1. Department of Pediatrics, Mount Sinai School of Medicine, New York, 10029, New York, USA

    Marco Tartaglia & Bruce D. Gelb

  2. Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York, 10029, New York, USA

    Ernest L. Mehler

  3. Department of Human Genetics, Mount Sinai School of Medicine, New York, 10029, New York, USA

    Bruce D. Gelb

  4. Laboratorio di Metabolismo e Biochimica Patologica, Istituto Superiore di Sanità, Rome, Italy

    Marco Tartaglia

  5. Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, 10461, New York, USA

    Rosalie Goldberg & Raju S. Kucherlapati

  6. Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Rome, Italy

    Giuseppe Zampino

  7. Department of Human Genetics, University Medical Centre, Nijmegen, The Netherlands

    Han G. Brunner, Hannie Kremer & Ineke van der Burgt

  8. Department of Medical Genetics, St George's Hospital Medical School, London, UK

    Andrew H. Crosby, Andra Ion, Steve Jeffery, Kamini Kalidas & Michael A. Patton

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  1. Marco Tartaglia
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Correspondence to Marco Tartaglia.

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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

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