Characterization of W1745C and S1783A: 2 novel mutations causing defective collagen binding in the A3 domain of von Willebrand factor.

摘要: Investigation of 3 families with bleeding symptoms demonstrated a defect in the collagen-binding activity von Willebrand factor (VWF) association normal VWF multimeric pattern. Genetic analysis showed affected persons to be heterozygous for mutations A3 domain VWF: S1731T, W1745C, and S1783A. One person compound heterozygosity W1745C R760H. S1783A have not been reported previously. The were reproduced by site-directed mutagenesis mutant expressed HEK293T cells. Collagen-binding measured immunosorbent assay varied according collagen type: associated pronounced binding both type I III collagen, whereas principal abnormality S1731T patients was reduction only. multimer pattern distribution proteins indistinguishable from wild-type recombinant VWF, confirming that resulted loss affinity at site impairment high-molecular-weight formation. Our findings demonstrate causing an may contribute clinically significant symptoms. We propose isolated defects are classified as distinct subtype disease.