Localization of the 8 point mutations found in the 67 VWD2B patients within the VWFA1 domain. We are using the modeling derived by the crystal structure of the VWF A1 domain.38 Seven gain-of-function VWD2B point mutations (H1268D, R1306Q, R1308C/L, I309V, V1316H, P1337L, R1341Q/W) are indicated in red, whereas the P1266L/Q is shown in yellow. Note that point mutation R1308 is indicated with 2 different colors according to the different amino acid substitutions: R1308C (red) and R1308L (yellow). For comparison, 4 loss-of-function mutations (delD1277, R1315C/L, Y1321C, R1374H) that were detected in patients with VWD2M are indicated in green. Note that both gain-of-function (VWD2B) and loss-of-function (VWD2M) mutations were characterized by VWF–GPIb-α/BC > 1. Only 2 point mutations, 1 with 2 different amino acid substitutions (P1266L/Q) and the other with 1 specific amino acid (R1308L), are indicated in yellow because they showed VWF–GPIb-α/BC values similar to normal controls (Table 2; Figure 5A).
