Premium
Structural, Functional, and Clinical Characterization of a Novel PTPN11 Mutation Cluster Underlying Noonan Syndrome
Author(s) -
Pan Luca,
Bocchinfuso Gianfranco,
Flex Elisabetta,
Rossi Cesare,
Baldassarre Giuseppina,
Lissewski Christina,
Pantaleoni Francesca,
Consoli Federica,
Lepri Francesca,
Magliozzi Monia,
Anselmi Massimiliano,
Delle Vigne Silvia,
Sorge Giovanni,
Karaer Kadri,
Cuturilo Goran,
Sartorio Alessandro,
Tinschert Sigrid,
Accadia Maria,
Digilio Maria C.,
Zampino Giuseppe,
Luca Alessandro,
Cavé Hélène,
Zenker Martin,
Gelb Bruce D.,
Dallapiccola Bruno,
Stella Lorenzo,
Ferrero Giovanni B.,
Martinelli Simone,
Tartaglia Marco
Publication year - 2017
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23175
Subject(s) - noonan syndrome , ptpn11 , biology , genetics , mutation , cluster (spacecraft) , computational biology , gene , kras , computer science , programming language
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 Leu 261 , Leu 262 , and Arg 265 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 Leu 262 and Arg 265 exerted by disruption of the N‐SH2/PTP autoinhibitory interaction. Molecular dynamics simulations suggested a more complex behavior for changes affecting Leu 261 , 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.