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

Risultato della ricerca: Contributo in rivistaArticolo in rivista

25 Citazioni (Scopus)


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 Arg265 in 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 Leu262 and Arg265 exerted 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.
Lingua originaleEnglish
pagine (da-a)451-459
Numero di pagine9
RivistaHuman Mutation
Stato di pubblicazionePubblicato - 2017


  • Genetics
  • Genetics (clinical)
  • Noonan syndrome
  • PTPN11 mutations
  • genotype-phenotype correlation analysis
  • structural and functional studies


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