VWD2M, INCLUDED
VON WILLEBRAND DISEASE, TYPE 2B, INCLUDED
VWD2N, INCLUDED
VON WILLEBRAND DISEASE, TYPE 2N, INCLUDED
VWD, TYPE 2 VON WILLEBRAND DISEASE, TYPE 2A, INCLUDED
VON WILLEBRAND DISEASE, TYPE II
VON WILLEBRAND DISEASE, TYPE 2M, INCLUDED
VWD2B, INCLUDED
VWD2A, INCLUDED
VWD2
Von Willebrand disease is the most common inherited bleeding disorder. It is characterized clinically by mucocutaneous bleeding, such as epistaxis and menorrhagia, and prolonged bleeding after surgery or trauma. It results from a defect in platelet aggregation due ... Von Willebrand disease is the most common inherited bleeding disorder. It is characterized clinically by mucocutaneous bleeding, such as epistaxis and menorrhagia, and prolonged bleeding after surgery or trauma. It results from a defect in platelet aggregation due to defects in the von Willebrand factor. Von Willebrand factor is a large, multimeric protein that plays a role in platelet adhesion and also serves as a carrier for the thrombotic protein factor VIII (F8; 300841). F8 is mutated in hemophilia A (306700) (review by Goodeve, 2010). Whereas von Willebrand disease types 1 (193400) and 3 (277480) are characterized by quantitative defects in the VWF gene, von Willebrand disease type 2, which is divided in subtypes 2A, 2B, 2M, and 2N, is characterized by qualitative abnormalities of the VWF protein. The mutant VWF protein in types 2A, 2B, and 2M are defective in their platelet-dependent function, whereas the mutant protein in type 2N is defective in its ability to bind F8. VWD2 accounts for 20 to 30% of cases of VWD (Mannucci, 2004; Sadler et al., 2006; Lillicrap, 2009; Goodeve, 2010). For a general discussion and a classification of the types of von Willebrand disease, see VWD type 1 (193400).
Von Willebrand disease type 2, like VWD type 1, is characterized by excessive mucocutaneous bleeding, such as epistaxis and menorrhagia, and prolonged bleeding after surgery (Mannucci, 2004). The delineation of different subtypes of VWD type 2 does not ... Von Willebrand disease type 2, like VWD type 1, is characterized by excessive mucocutaneous bleeding, such as epistaxis and menorrhagia, and prolonged bleeding after surgery (Mannucci, 2004). The delineation of different subtypes of VWD type 2 does not reflect clinical differences, but rather different mutant VWF protein phenotypes, which may affect diagnosis, treatment, and counseling (Sadler et al., 2006).
Mutations causing the enhanced proteolysis phenotype lie within or near domain A2 (exon 28) of the VWF gene, which is the site of the ADAMTS13 (604134) cleavage sequence between residues ... - Von Willebrand Disease Type 2A Mutations causing the enhanced proteolysis phenotype lie within or near domain A2 (exon 28) of the VWF gene, which is the site of the ADAMTS13 (604134) cleavage sequence between residues tyr1605 and met1606. Mutations interfering with multimerization occur in regions involved in dimer or multimer assembly, such as the VWF propeptide, the N-terminal D3 domain, the A2 domain, and the C terminus (James and Lillicrap, 2008). In affected members of a family with von Willebrand disease type 2A, Iannuzzi et al. (1991) identified a 4883T-C heterozygous mutation in the VWF (I865T; 613160.0001). The I865R substitution was located immediately adjacent to 2 other previously identified mutations that also result in type 2A von Willebrand disease (R834W, 613160.0002 and V844D, 613160.0003; Ginsburg et al., 1989), suggesting a clustering for these mutations in a portion of the protein critical for proteolysis. Dent et al. (1990) noted that the I865T, R834W, and V844D mutations are located within a 32-amino acid segment in the midportion of the 2,813-amino acid VWF coding sequence. Type 2A von Willebrand disease is characterized by normal or only moderately decreased levels of von Willebrand factor, the absence of large and intermediate VWF multimers, and increased VWF proteolysis with an increase in the plasma levels of the 176-kD VWF proteolytic fragment. The ADAMTS13 (604134) proteolytic-cleavage site is located between tyr842 and met843 (numbering based on the mature protein). - Von Willebrand Disease Type 2A/IIE Schneppenheim et al. (2010) reported a high frequency (29%) of VWD type 2A subtype IIE among patients with type 2A studied in their laboratory. Type IIE is associated with a reduction of high molecular weight (HMW) VWF multimers and a lack of outer proteolytic bands on gel electrophoresis, indicating reduced proteolysis. Genetic analysis of 38 such index cases identified 22 different mutations in the VWF gene, most of them affecting cysteine residues clustered in the D3 domain. The most common mutation was Y1146C (613160.0039), which was found in 12 (32%) probands. In vitro expression studies indicated that the Y1146C-mutant protein caused a severe reduction in or lack of HMW monomers and decreased secreted VWF antigen levels. However, clinical symptoms were heterogeneous among carriers, ranging from mild to severe bleeding. Schneppenheim et al. (2010) suggested that several mechanisms likely act in concert to produce subtype IIE, including decreased secretion of VWF, the change of a cysteine residue which may impact multimerization, and decreased half-life of the mutant protein. Altered ADAMTS13-mediated proteolysis did not appear to be a major primary factor. - Von Willebrand Disease Type 2B Mutations causing VWD type 2B tend to cluster within or near the A1 domain of the VWF gene, which mediates platelet GP1BA (606672) binding. The mutations appear to enhance platelet binding of VWF by stabilizing the bound conformation (Sadler et al., 2006). In patients with VWD type 2B, Randi et al. (1991) identified 3 different heterozygous mutations in exon 28 of the VWF gene (613160.0005-613160.0007) within the domain that interacts with platelet glycoprotein GP1BA, resulting in a loss of function. Patient plasma showed a decrease in large VWF multimers due to spontaneous binding of VWF to platelets and subsequent clearance from the circulation. The region of VWF that binds to GP1BA has been localized to a peptide including amino acids 480 to 718 of the mature subunit that is encoded by exon 28. In affected members of a Swedish family (Holmberg et al., 1986) and a German family with a variant of VWD type 2B, Holmberg et al. (1993) identified a heterozygous mutation in the VWF gene (P1266L; 613160.0033). The phenotype was unique in that there was a mild bleeding disorder, and laboratory studies showed that platelets aggregated at much lower ristocetin concentrations than normal. - Von Willebrand Disease Type 2M In a French mother and son with VWD type 2M, Stepanian et al. (2003) identified a heterozygous mutation in the VWF gene (S1285F; 613160.0030) that altered the folding of the A1 loop and prevented the correct exposure of VWF binding sites to GP1BA. The findings were consistent with a loss of function. - Von Willebrand Disease Type 2N Mutations that cause VWD type 2N usually occur in the F8-binding site of VWF, which lies between ser764 and arg1035. However, mutations outside of this region have also been reported (Hilbert et al., 2004). In a 50-year-old French woman with VWD type 2N reported by Mazurier et al. (1990), Gaucher et al. (1991) identified a homozygous mutation in the VWF gene (T28M in the mature subunit; 613160.0011). Mazurier et al. (2002) reported a 20-year-old French woman with VWD type 2N who was compound heterozygosity for 2 mutations in the VWF gene (Y357X, 613160.0035 and C1060R, 613160.0036). She had very low levels of VWF and F8, and absent binding of VWF to F8. Clinical features included epistaxis, hematomas, and hematemesis throughout childhood. The diagnosis was complicated at first because 2 male first cousins had F8 deficiency (306700) due to a hemizygous mutation in the F8 gene (C179G; 300841.0268). Hilbert et al. (2004) reported 2 unrelated French patients with type 2N VWD who were compound heterozygous for R854Q (613160.0014) and another pathogenic mutation (Y795C, 613160.0031 and C804F, 613160.0032, respectively). - Von Willebrand Disease Type 2CB In affected members of 2 unrelated families with von Willebrand disease type 2CB, Riddell et al. (2009) identified heterozygous mutations in the collagen-binding A3 domain of the VWF gene (W1745C; 613160.0040 and S1783A; 613160.0042, respectively). The authors noted that VWD type 2M is associated with mutations in the A1 domain of VWF.