A VWF missense variant in Havanese dogs with type 3 von Willebrand disease.

Quantitative and functional defects of von Willebrand Factor (VWF) cause the hereditary bleeding disorder von Willebrand disease (VWD). Three types of VWD exist; type 3 is the most severe and rare, characterized by an almost complete absence of VWF protein. In this study, we investigated the cause of type 3 VWD in a family of purebred Havanese dogs. Pedigree analysis suggested an autosomal recessive mode of inheritance. We performed whole genome sequencing of the parents and relatives of two affected siblings, revealing a novel missense variant in the VWF gene. The variant causes a cysteine to glycine substitution at residue 2571 (NP_001002932.1:p.(Cys2571Gly)) within the VWF C4 domain. This residue is highly conserved across vertebrates and plays a critical role in maintaining the structural integrity of VWF through disulfide bonds. This change probably disrupts the conformation of the C4 domain, leading to VWF concentrations undetectable by enzyme-linked immunosorbent assay in affected dogs. Genotyping confirmed an autosomal recessive mode of inheritance, and the variant was found exclusively within the family. Our findings provide new insights into the genetic basis of VWD and highlight the importance of conserved cysteine residues for VWF stability.