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Papers In Press, published online ahead of print December 23, 2005
Medicine, Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02115
Corresponding Author: mkontari{at}bidmc.harvard.edu
Multiple Lentigenes/LEOPARD syndrome (LS) is a rare, autosomal dominant disorder characterized by Lentigines, ECG abnormalities, Ocular hypertelorism, Pulmonic valvular stenosis, Abnormalities of genitalia, Retardation of growth, and Deafness. Like the more common Noonan Syndrome (NS), LS is caused by germ line missense mutations in PTPN11, encoding the protein-tyrosine phosphatase Shp2. Enzymologic, structural, cell biological, and mouse genetic studies indicate that NS is caused by gain-of-function PTPN11 mutations. Because NS and LS share several features, LS has been viewed as an NS variant. We examined a panel of LS mutants, including the two most common alleles. Surprisingly, we found that in marked contrast to NS, LS mutants are catalytically defective and act as dominant negative mutations that interfere with growth factor/Erk-MAPK mediated signaling. Molecular modeling and biochemical studies suggest that LS mutations contort the Shp2 catalytic domain and result in open, inactive forms of Shp2. Our results establish that the pathogenesis of LS and NS is distinct, and suggest that these disorders should be distinguished by mutational analysis rather than clinical presentation.
J. Biol. Chem, 10.1074/jbc.M513068200
Submitted on December 7, 2005
Accepted on December 23, 2005
PTPN11 (SHP2) mutations in leopard syndrome have dominant negative, not activating, effects
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