title: Structural, Functional, and Clinical Characterization of a Novel PTPN11 Mutation Cluster Underlying Noonan Syndrome.
abstract: 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.
authors.affiliation: Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.|Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.|Dipartimento di Medicina Sperimentale, Sapienza Università di Roma, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Pannone
authors.affiliation: Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma Tor Vergata, Rome, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Bocchinfuso
authors.affiliation: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Flex
authors.affiliation: Genetica Medica, Policlinico S. Orsola-Malpighi, Bologna, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Rossi
authors.affiliation: Department of Pediatric and Public Health Sciences, University of Torino, Torino, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Baldassarre
authors.affiliation: Institute of Human Genetics, University Hospital of Magdeburg, Otto-von-Guericke-University, Magdeburg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Lissewski
authors.affiliation: Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pantaleoni
authors.affiliation: Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Consoli
authors.affiliation: Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Lepri
authors.affiliation: Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.|Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy.
authors.forename: Monia
authors.initials: M
authors.lastname: Magliozzi
authors.affiliation: Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma Tor Vergata, Rome, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Anselmi
authors.affiliation: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Delle Vigne
authors.affiliation: Unità Operativa Complessa di Clinica Pediatrica, Dipartimento di Medicina Clinica e Sperimentale, Università di Catania, Catania, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sorge
authors.affiliation: Dr. Ersin Arslan Research and Training Hospital, Department of Medical Genetics, Gaziantep, Turkey.
authors.forename: Kadri
authors.initials: K
authors.lastname: Karaer
authors.affiliation: Faculty of Medicine, University of Belgrade, Belgrade, Serbia.|University Children's Hospital, Belgrade, Serbia.
authors.forename: Goran
authors.initials: G
authors.lastname: Cuturilo
authors.affiliation: Istituto Auxologico Italiano, Experimental Laboratory for Auxo-Endocrinological Research, Milan and Verbania, Italy.|Istituto Auxologico Italiano, Division of Auxology, Verbania, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sartorio
authors.affiliation: Institute of Clinical Genetics, Technical University of Dresden, Dresden, Germany.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Tinschert
authors.affiliation: Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Accadia
authors.affiliation: Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Digilio
authors.affiliation: Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zampino
authors.affiliation: Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: De Luca
authors.affiliation: Département de Génétique, Hôpital Robert Debré, Paris, France.|INSERM UMR_S1131, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris-Sorbonne-Cité, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Cavé
authors.affiliation: Institute of Human Genetics, University Hospital of Magdeburg, Otto-von-Guericke-University, Magdeburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.affiliation: Mindich Child Health and Development Institute and Departments of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
authors.affiliation: Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.affiliation: Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma Tor Vergata, Rome, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Stella
authors.affiliation: Department of Pediatric and Public Health Sciences, University of Torino, Torino, Italy.
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Ferrero
authors.affiliation: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Martinelli
authors.affiliation: Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
mesh_terms: D020022:Genetic Predisposition to Disease / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D020125:Mutation, Missense; D009634:Noonan Syndrome / Q000235:genetics* / Q000473:pathology; D011485:Protein Binding; D000072417:Protein Domains; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018909:src Homology Domains
chemical_list: C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
keywords: Noonan syndrome; PTPN11 mutations; genotype-phenotype correlation analysis; structural and functional studies