کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2812551 1569313 2006 12 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Diversity and Functional Consequences of Germline and Somatic PTPN11 Mutations in Human Disease
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی ژنتیک
پیش نمایش صفحه اول مقاله
Diversity and Functional Consequences of Germline and Somatic PTPN11 Mutations in Human Disease
چکیده انگلیسی

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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: - Volume 78, Issue 2, February 2006, Pages 279–290
نویسندگان
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