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

Hum Mutat. 2017 Apr;38(4):451-459. doi: 10.1002/humu.23175.

Luca Pannone ¹ ² ³, Gianfranco Bocchinfuso ⁴, Elisabetta Flex ², Cesare Rossi ⁵, Giuseppina Baldassarre ⁶, Christina Lissewski ⁷, Francesca Pantaleoni ¹, Federica Consoli ⁸, Francesca Lepri ¹, Monia Magliozzi ¹ ⁸, Massimiliano Anselmi ⁴, Silvia Delle Vigne ², Giovanni Sorge ⁹, Kadri Karaer ¹⁰, Goran Cuturilo ¹¹ ¹², Alessandro Sartorio ¹³ ¹⁴, Sigrid Tinschert ¹⁵, Maria Accadia ⁸, Maria C Digilio ¹, Giuseppe Zampino ¹⁶, Alessandro De Luca ⁸, Hélène Cavé ¹⁷ ¹⁸, Martin Zenker ⁷, Bruce D Gelb ¹⁹, Bruno Dallapiccola ¹, Lorenzo Stella ⁴, Giovanni B Ferrero ⁶, Simone Martinelli ², Marco Tartaglia ¹

Affiliations

1 Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
2 Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
3 Dipartimento di Medicina Sperimentale, Sapienza Università di Roma, Rome, Italy.
4 Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma Tor Vergata, Rome, Italy.
5 Genetica Medica, Policlinico S. Orsola-Malpighi, Bologna, Italy.
6 Department of Pediatric and Public Health Sciences, University of Torino, Torino, Italy.
7 Institute of Human Genetics, University Hospital of Magdeburg, Otto-von-Guericke-University, Magdeburg, Germany.
8 Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy.
9 Unità Operativa Complessa di Clinica Pediatrica, Dipartimento di Medicina Clinica e Sperimentale, Università di Catania, Catania, Italy.
10 Dr. Ersin Arslan Research and Training Hospital, Department of Medical Genetics, Gaziantep, Turkey.
11 Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
12 University Children's Hospital, Belgrade, Serbia.
13 Istituto Auxologico Italiano, Experimental Laboratory for Auxo-Endocrinological Research, Milan and Verbania, Italy.
14 Istituto Auxologico Italiano, Division of Auxology, Verbania, Italy.
15 Institute of Clinical Genetics, Technical University of Dresden, Dresden, Germany.
16 Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Rome, Italy.
17 Département de Génétique, Hôpital Robert Debré, Paris, France.
18 INSERM UMR_S1131, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris-Sorbonne-Cité, Paris, France.
19 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.

PMID: 28074573 DOI: 10.1002/humu.23175

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 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.

Keywords

Noonan syndrome; PTPN11 mutations; genotype-phenotype correlation analysis; structural and functional studies.

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