Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 78, Issue 2, Pages 279-290Publisher
CELL PRESS
DOI: 10.1086/499925
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Funding
- NCI NIH HHS [CA095621, R01 CA095621] Funding Source: Medline
- NHLBI NIH HHS [HL074728, P50 HL074728, HL71207, R01 HL071207] Funding Source: Medline
- NICHD NIH HHS [HD01294, K24 HD001294] Funding Source: Medline
- Telethon [GGP04172] Funding Source: Medline
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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.
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