title: Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease.
abstract: Germline mutations in PTPN11, the gene encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome (NS) and the clinically related LEOPARD syndrome (LS), whereas somatic mutations in the same gene contribute to leukemogenesis. On the basis of our previously gathered genetic and biochemical data, we proposed a model that splits NS- and leukemia-associated PTPN11 mutations into two major classes of activating lesions with differential perturbing effects on development and hematopoiesis. To test this model, we investigated further the diversity of germline and somatic PTPN11 mutations, delineated the association of those mutations with disease, characterized biochemically a panel of mutant SHP-2 proteins recurring in NS, LS, and leukemia, and performed molecular dynamics simulations to determine the structural effects of selected mutations. Our results document a strict correlation between the identity of the lesion and disease and demonstrate that NS-causative mutations have less potency for promoting SHP-2 gain of function than do leukemia-associated ones. Furthermore, we show that the recurrent LS-causing Y279C and T468M amino acid substitutions engender loss of SHP-2 catalytic activity, identifying a previously unrecognized behavior for this class of missense PTPN11 mutations.
authors.affiliation: Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanita, Rome, Italy. mtartaglia@iss.it
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.forename: Simone
authors.initials: S
authors.lastname: Martinelli
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Stella
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Bocchinfuso
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Flex
authors.forename: Viviana
authors.initials: V
authors.lastname: Cordeddu
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zampino
authors.forename: Ineke van der
authors.initials: Iv
authors.lastname: Burgt
authors.forename: Antonio
authors.initials: A
authors.lastname: Palleschi
authors.forename: Tamara C
authors.initials: TC
authors.lastname: Petrucci
authors.forename: Mariella
authors.initials: M
authors.lastname: Sorcini
authors.forename: Claudia
authors.initials: C
authors.lastname: Schoch
authors.forename: Robin
authors.initials: R
authors.lastname: Foa
authors.forename: Peter D
authors.initials: PD
authors.lastname: Emanuel
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D015331:Cohort Studies; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics*; D044542:LEOPARD Syndrome / Q000235:genetics*; D007938:Leukemia / Q000235:genetics*; D008297:Male; D009154:Mutation; D009634:Noonan Syndrome / Q000235:genetics*; D011487:Protein Conformation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases