Structural, Functional, and Clinical Characterization of a Novel PTPN11 Mutation Cluster Underlying Noonan Syndrome

Luca Pannone, Gianfranco Bocchinfuso, Elisabetta Flex, Cesare Rossi, Giuseppina Baldassarre, Christina Lissewski, Francesca Pantaleoni, Federica Consoli, Francesca Lepri, Monia Magliozzi, Massimiliano Anselmi, Silvia Delle Vigne, Giovanni Sorge, Kadri Karaer, Goran Cuturilo, Alessandro Sartorio, Sigrid Tinschert, Maria Accadia, Maria C Digilio, Giuseppe ZampinoAlessandro De Luca, Hélène Cavé, Martin Zenker, Bruce D Gelb, Bruno Dallapiccola, Lorenzo Stella, Giovanni B Ferrero, Simone Martinelli, Marco Tartaglia

Research output: Contribution to journalArticlepeer-review


Germline mutations in PTPN11, the gene encoding the Src-homology 2 (SH2) domain-containing protein tyrosine phosphatase (SHP2), cause Noonan syndrome (NS), a relatively common, clinically variable, multisystem disorder. Here, we report on the identification of five different PTPN11 missense changes affecting residues Leu261, Leu262, and Arg265in 16 unrelated individuals with clinical diagnosis of NS or with features suggestive for this disorder, specifying a novel disease-causing mutation cluster. Expression of the mutant proteins in HEK293T cells documented their activating role on MAPK signaling. Structural data predicted a gain-of-function role of substitutions at residues Leu262and Arg265exerted by disruption of the N-SH2/PTP autoinhibitory interaction. Molecular dynamics simulations suggested a more complex behavior for changes affecting Leu261, with possible impact on SHP2's catalytic activity/selectivity and proper interaction of the PTP domain with the regulatory SH2 domains. Consistent with that, biochemical data indicated that substitutions at codons 262 and 265 increased the catalytic activity of the phosphatase, while those affecting codon 261 were only moderately activating but impacted substrate specificity. Remarkably, these mutations underlie a relatively mild form of NS characterized by low prevalence of cardiac defects, short stature, and cognitive and behavioral issues, as well as less evident typical facial features.

Original languageEnglish
Pages (from-to)451-459
Number of pages9
JournalHuman Mutation
Issue number4
Publication statusPublished - Apr 2017


  • Genetic Predisposition to Disease/genetics
  • HEK293 Cells
  • Humans
  • MAP Kinase Signaling System/genetics
  • Models, Molecular
  • Mutation
  • Mutation, Missense
  • Noonan Syndrome/genetics
  • Protein Binding
  • Protein Domains
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11/chemistry
  • src Homology Domains


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