Document Detail

Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease.
MedLine Citation:
PMID:  16358218     Owner:  NLM     Status:  MEDLINE    
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.
Marco Tartaglia; Simone Martinelli; Lorenzo Stella; Gianfranco Bocchinfuso; Elisabetta Flex; Viviana Cordeddu; Giuseppe Zampino; Ineke van der Burgt; Antonio Palleschi; Tamara C Petrucci; Mariella Sorcini; Claudia Schoch; Robin Foa; Peter D Emanuel; Bruce D Gelb
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2005-12-07
Journal Detail:
Title:  American journal of human genetics     Volume:  78     ISSN:  0002-9297     ISO Abbreviation:  Am. J. Hum. Genet.     Publication Date:  2006 Feb 
Date Detail:
Created Date:  2006-01-09     Completed Date:  2007-11-06     Revised Date:  2012-02-23    
Medline Journal Info:
Nlm Unique ID:  0370475     Medline TA:  Am J Hum Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  279-90     Citation Subset:  IM    
Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanita, Rome, Italy.
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MeSH Terms
Amino Acid Sequence
Cohort Studies
Germ-Line Mutation
Intracellular Signaling Peptides and Proteins / chemistry,  genetics*
LEOPARD Syndrome / genetics*
Leukemia / genetics*
Noonan Syndrome / genetics*
Protein Conformation
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Protein Tyrosine Phosphatases / chemistry,  genetics*
Grant Support
Reg. No./Substance:
0/Intracellular Signaling Peptides and Proteins; EC protein, human; EC Tyrosine Phosphatase, Non-Receptor Type 11; EC Tyrosine Phosphatases

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