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

Marco Tartaglia, Ernest L. Mehler, Rosalie Goldberg, Giuseppe Zampino, Han G. Brunner, Hannie Kremer, Ineke Van Der Burgt, Andrew H. Crosby, Andra Ion, Steve Jeffery, Kamini Kalidas, Michael A. Patton, Raju S. Kucherlapati, Bruce D. Gelb

Risultato della ricerca: Contributo in rivistaArticolo in rivista

1201 Citazioni (Scopus)


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). 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 (NS1) [corrected] on chromosome 12q24.1, and genetic heterogeneity has also been documented. 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.
Lingua originaleEnglish
pagine (da-a)465-468
Numero di pagine4
RivistaNature Genetics
Stato di pubblicazionePubblicato - 2001


  • Chromosomes, Human, Pair 12
  • Genetic Heterogeneity
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation, Missense
  • Noonan Syndrome
  • Protein Conformation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases


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