Diversity and Functional Consequences of Germline and Somatic PTPN11 Mutations in Human Disease

摘要: Germline mutations in PTPN11, the gene encoding protein tyrosine phosphatase SHP-2, cause Noonan syndrome (NS) and clinically related LEOPARD (LS), whereas somatic same contribute to leukemogenesis. On basis of our previously gathered genetic biochemical data, we proposed a model that splits NS- leukemia-associated PTPN11 into two major classes activating lesions with differential perturbing effects on development hematopoiesis. To test this model, investigated further diversity germline mutations, delineated association those disease, characterized biochemically panel mutant SHP-2 proteins recurring NS, LS, leukemia, performed molecular dynamics simulations determine structural selected mutations. Our results document strict correlation between identity lesion disease demonstrate NS-causative have less potency for promoting gain function than do ones. Furthermore, show recurrent LS-causing Y279C T468M amino acid substitutions engender loss catalytic activity, identifying unrecognized behavior class missense