Novel Likely Pathogenic Variant in the A3 Domain of von Willebrand Factor Leading to a Collagen-Binding Defect

Abstract

Von Willebrand disease (VWD) is the most prevalent congenital bleeding disorder. Diagnosis and classification of VWD is complex due to its heterogeneity regarding clinical manifestations and molecular genetic analysis. Genetic investigations became an inherent part of diagnosis and help distinguish different types/subtypes of VWD. Although many variants have been listed being causative for VWD, the genetic etiology remains undefined in a lot of patients. We report about two siblings with severely reduced values for von Willebrand factor collagen-binding activity (VWF:CB). Genetic analysis using panel sequencing identified a heterozygous non-synonymous single nucleotide variant in exon 30. At the protein level, the alteration (p.Ser1731Leu) is located in the A3 collagen-binding domain. The amino acid position is already known to be important for collagen binding because p.Ser1731Thr has been reported to affect the VWF:CB.

Keywords

von Willebrand factor - von Willebrand disease - type 2M - collagen-binding domain

Publikationsverlauf

Eingereicht: 14. Juli 2021

Angenommen: 19. November 2021

Artikel online veröffentlicht:
01. Februar 2022

• References

• 1 Lankhof H, van Hoeij M, Schiphorst ME. et al. A3 domain is essential for interaction of von Willebrand factor with collagen type III. Thromb Haemost 1996; 75 (06) 950-958
• 2 Riddell AF, Gomez K, Millar CM. et al. Characterization of W1745C and S1783A: 2 novel mutations causing defective collagen binding in the A3 domain of von Willebrand factor. Blood 2009; 114 (16) 3489-3496
• 3 Ribba AS, Loisel I, Lavergne JM. et al. Ser968Thr mutation within the A3 domain of von Willebrand factor (VWF) in two related patients leads to a defective binding of VWF to collagen. Thromb Haemost 2001; 86 (03) 848-854