Alexandre Irrthum, Marika J

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Congenital Hereditary Lymphedema Caused by a Mutation That Inactivates VEGFR3 Tyrosine Kinase Alexandre Irrthum, Marika J. Karkkainen, Koen Devriendt, Kari Alitalo, Miikka Vikkula The American Journal of Human Genetics Volume 67, Issue 2, Pages 295-301 (August 2000) DOI: 10.1086/303019 Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 1 A, Pedigree of the family with inherited congenital lymphedema. Blackened symbols represent affected individuals. B, Deduced haplotypes for three markers in 5q34-35. FLT4I, VEGFR3 intragenic polymorphism. Haplotype transmitted with disorder is boxed. C, Autoradiogram of the intragenic FLT4I marker. D, Allele-specific PCR for the A3123G mutation. Lower band, mutated allele. Upper band, internal control for PCR. The American Journal of Human Genetics 2000 67, 295-301DOI: (10.1086/303019) Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 2 Autoradiogram showing sequences of two clones corresponding to wild-type (W) and mutant (M) alleles in individual I.1. Small letters, intronic sequence; capital letters, exonic sequence. * = mutation. The American Journal of Human Genetics 2000 67, 295-301DOI: (10.1086/303019) Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 3 Effect of H1035R mutation on tyrosyl autophosphorylation of VEGFR3. Expression plasmids for WT and mutant VEGFR3 were transfected into 293T human embryonic kidney cells (lanes 1:0 and 0:1, respectively) or cotransfected using 3:1, 1:1, and 1:3 ratios of WT to mutant plasmid. Receptor phosphorylation was analyzed from VEGFR3 immunoprecipitates by western blotting using antiphosphotyrosine antibodies (P-Tyr, upper part). Total amount of receptor protein is shown in VEGFR3 western blotting (lower part). Sizes on the right correspond to four different forms of VEGFR3 (see text). The American Journal of Human Genetics 2000 67, 295-301DOI: (10.1086/303019) Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 4 A, Amino acid sequence alignment for seven different human tyrosine-kinase receptors. Conserved catalytic loop residues are highlighted with gray background. ↑ = mutated histidine (H1035R). Δ = residue mutated in KIT causing piebaldism (R→G). * = catalytic aspartate. B, Crystal structure of VEGFR2, a tyrosine kinase receptor homologous to VEGFR3. Histidine residue mutated in VEGFR3 receptor of patients with lymphedema shown in black. The kinase activation loop was disordered in the crystal and is not shown. The American Journal of Human Genetics 2000 67, 295-301DOI: (10.1086/303019) Copyright © 2000 The American Society of Human Genetics Terms and Conditions