PTPN11 Mutations in Noonan Syndrome: Molecular Spectrum, Genotype-Phenotype Correlation, and Phenotypic Heterogeneity Marco Tartaglia, Kamini Kalidas,

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PTPN11 Mutations in Noonan Syndrome: Molecular Spectrum, Genotype-Phenotype Correlation, and Phenotypic Heterogeneity Marco Tartaglia, Kamini Kalidas, Adam Shaw, Xiaoling Song, Dan L. Musat, Ineke van der Burgt, Han G. Brunner, Débora R. Bertola, Andrew Crosby, Andra Ion, Raju S. Kucherlapati, Steve Jeffery, Michael A. Patton, Bruce D. Gelb The American Journal of Human Genetics Volume 70, Issue 6, Pages 1555-1563 (June 2002) DOI: 10.1086/340847 Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 1 Cosegregation of PTPN11 mutations and Noonan phenotype. A, Restriction analysis of PTPN11 PCR product containing exon 8, showing segregation of the 922A→G mutation in the original large family with NS that shows linkage to 12q24 (Jamieson et al. 1994). The family tree is shown above. The mutation introduces an EcoRV restriction site, resulting in 246- and 366-bp products, whereas the wild-type allele remains undigested (612 bp). B, DHPLC elution profiles of PTPN11 exon 8 PCR products, showing segregation of the 923A→G change in a family inheriting Noonan-like/multiple giant-cell lesion syndrome (Bertola et al. 2001). A single peak characterizes the wild-type profile, and a variant profile, characterized by two peaks, is observed in all affected family members. The family tree is shown on the left. The gray-shaded symbol indicates an indeterminate phenotype. The American Journal of Human Genetics 2002 70, 1555-1563DOI: (10.1086/340847) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 2 Location of mutated residues in SHP-2 in the inactive conformation: Cα trace of the N-SH2 (thin blue line), C-SH2 (thin magenta line), and PTP (thin orange line) domains; and N-SH2/C-SH2 and C-SH2/PTP linkers (thin gray lines), according to Hof et al. (1998). The views represented in panels A and B are orthogonal to each other. Mutated residues are indicated with their side chains as thick lines (N-SH2 residues located in or close to the N-SH2/PTP interaction surface are shown in white; linker, C-SH2, and N-SH2-phosphopeptide binding residues are shown in green; and PTP residues located in or close to the N-SH2/PTP interaction surface are shown in red). The American Journal of Human Genetics 2002 70, 1555-1563DOI: (10.1086/340847) Copyright © 2002 The American Society of Human Genetics Terms and Conditions