Alternative titles; symbols
HGNC Approved Gene Symbol: VWF
SNOMEDCT: 128106003, 128108002, 359711001, 359717002, 359732009; ICD10CM: D68.01, D68.020, D68.021, D68.022, D68.023, D68.03;
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38): 12:5,948,877-6,124,670 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p13.31 | von Willebrand disease, type 1 | 193400 | Autosomal dominant | 3 |
| von Willebrand disease, type 3 | 277480 | Autosomal recessive | 3 | |
| von Willebrand disease, types 2A, 2B, 2M, and 2N | 613554 | Autosomal dominant; Autosomal recessive | 3 |
The VWF gene encodes von Willebrand factor (VWF), a large multimeric glycoprotein that plays a central role in the blood coagulation system, serving both as a major mediator of platelet-vessel wall interaction and platelet adhesion, and as a carrier for coagulation factor VIII (F8; 300841). Diminished or abnormal VWF activity results in von Willebrand disease (VWD; see 193400), a common and complex hereditary bleeding disorder (Ginsburg et al., 1985).
The receptor for von Willebrand factor is a large complex comprising 4 proteins: glycoprotein Ib (GP1BA; 606672 and GP1BB; 138720), platelet glycoprotein IX (GP9; 173515) and platelet glycoprotein V (GP5; 173511).
Ginsburg et al. (1985) isolated overlapping cDNA clones corresponding to the human VWF gene. The 8.2-kb transcript accounted for approximately 0.3% of endothelial cell mRNA, but was undetectable in several other tissues examined.
Sadler et al. (1985) isolated cDNA clones from cultured human umbilical vein endothelial cells. Two inserts, which together coded for about 80% of the protein, were identified. One corresponded to residues 1 to 110 of the circulating mature protein and the second coded for 1,525 residues at the C terminus; there was about a 350-residue gap between the 2 clones. At least 3 separate polypeptide segments showed evidence of internal duplication, suggesting a complex evolutionary history. The full-length mature protein contains 2,050 amino acids (Titani et al., 1986).
Bonthron et al. (1986) presented the nucleotide sequence of pre-pro-von Willebrand factor cDNA.
Lynch et al. (1985) also cloned the VWF gene, and Lynch et al. (1986) stated that 4 separate groups had reported isolation of VWF-specific clones from human endothelial cell cDNA libraries.
VWF is synthesized in endothelial cells and megakaryocytes as a 2,813-residue pre-protein. It dimerizes, undergoes extensive posttranslational modification, and is packaged as a mature protein into endothelial cell Weibel-Palade bodies and platelet alpha granules. Endothelial cells secrete VWF constitutively, whereas platelets release VWF when stimulated. Circulating VWF multimers are composed of up to 40 subunits and range in size from 500 to 10,000 kD (review by Goodeve, 2010). VWF is synthesized in megakaryocytes and endothelial cells with a 22-amino acid signal peptide, 741-amino acid propeptide and 2,050-amino acid mature VWF (review by Goodeve, 2010).
Mancuso et al. (1989) concluded that the VWF gene is approximately 178 kb long and contains 52 exons. The exons vary from 40 to 1379 bp, and the introns from 97 bp to approximately 19.9 kb. The signal peptide and propeptide (von Willebrand antigen II) are encoded by 17 exons in approximately 80 kb of DNA, while the mature subunit of von Willebrand factor and the 3-prime noncoding region are encoded by 35 exons in the remainder of the gene. A number of repetitive sequences were identified, including 14 Alu repeats and a polymorphic TCTA simple repeat of about 670 bp in intron 40. Regions of the gene that encode homologous domains have similar structures, supporting a model for their origin by gene segment duplication.
From a study of a series of overlapping cosmid genomic clones of VWF, Collins et al. (1987) identified the transcription initiation site, a portion of the promoter region, and the translation termination codon. Their evidence supported the existence of a single VWF gene in the haploid genome.
Verweij et al. (1985) cloned the gene for VWF and assigned it to chromosome 12 using cDNA probes with panels of human-rodent hybrid cells.
By somatic cell hybridization and in situ hybridization using a cDNA clone of the gene, Ginsburg et al. (1985) assigned the VWF gene to 12pter-p12.
Shelton-Inloes et al. (1987) confirmed the localization of the gene to chromosome 12 and identified a homologous sequence on chromosome 22. The VWF gene is the most distally mapped gene on 12p13.3 (NIH/CEPH Collaborative Mapping Group, 1992).
Barrow et al. (1993) showed that the loci for neurotrophin-3 (NTF3; 162660) and von Willebrand factor map to 12p13 in the human and are closely linked on mouse chromosome 6.
Pseudogene
Mancuso et al. (1991) reported that the partially unprocessed pseudogene on chromosome 22q11-q13 is 21 to 29 kb long and corresponds to exons 23 to 34 of the VWF gene. They found splice site and nonsense mutations, suggesting that the pseudogene cannot yield functional transcripts. By in situ hybridization experiments on metaphase spreads from a Philadelphia-chromosome-positive chronic myelogenous leukemia (151410) patient, Patracchini et al. (1992) found that the pseudogene is located centromeric to the breakpoint cluster region.
Ruggeri (1997) reviewed VWF within a series on cell adhesion in vascular biology and took the opportunity to review the understanding of platelet function in hemostasis and thrombosis.
Sporn et al. (1987) found that the VWF released from endothelial cell Weibel-Palade bodies bound particularly avidly to the extracellular matrix. Wagner et al. (1991) showed that the VWF propolypeptide is necessary for the formation of the Weibel-Palade storage granules. Following secretagogue stimulation, Weibel-Palade bodies undergo exocytosis and release long VWF filaments, averaging 100 micrometers, that capture platelets along their length. Subsequent activation and aggregation of platelets cause the formation of a hemostatic plug (Michaux et al., 2006). Michaux et al. (2006) determined that the propeptide of VWF, which is released into the bloodstream at exocytosis, was involved in a pH-dependent interaction with the first 3 domains of mature VWF protein and this interaction was required for compact storage of VWF filaments. They showed that multimerization and tubular storage were a prerequisite for rapid unfurling of long VWF filaments in stimulated human umbilical vein endothelial cells in culture and in laser-injured cremaster venules in mice. If tubules were disassembled prior to exocytosis, short or tangled filaments were released and platelet recruitment was reduced. Michaux et al. (2006) concluded that compaction of VWF into tubules determines the rod-like shape of Weibel-Palade bodies and is critical to the protein's hemostatic function.
ADAMTS13 (604134) specifically cleaves a peptidyl bond between tyr1605 and met1606 in the A2 domain of VWF and thus acts to regulate VWF size. Kokame et al. (2004) identified a 73-amino acid peptide, which they designated VWF73, as the minimal VWF substrate cleavable by ADAMTS13. VWF73 contains asp1596 to arg1668 of VWF.
Wu et al. (2006) cleaved VWF73 into shorter peptides and found that a 24-amino acid peptide encompassing pro1645 to lys1668 was the shortest peptide that could bind ADAMTS13 and competitively inhibit its cleavage of a VWF-derived substrate. This peptide and longer peptides containing this core sequence also inhibited cleavage of multimeric VWF by ADAMTS13. These results suggested the presence of a complementary extended binding site, or exosite, on ADAMTS13. Asp1653-to-ala and asp1663-to-ala mutations in the VWF-derived substrate significantly reduced the rate of cleavage of the substrate peptide by ADAMTS13, whereas a glu1655-to-ala mutation significantly enhanced the rate of cleavage. Wu et al. (2006) concluded that ionic interactions between the exosite on ADAMTS13 and a region of VWF spanning pro1645 to lys1668 play a significant role in substrate recognition.
Cao et al. (2008) showed that, under shear stress and at physiologic pH and ionic strength, coagulation factor VIII (F8; 300841) accelerated, by a factor of about 10, the rate of ADAMTS13-mediated cleavage of the tyr1605/met1606 bond in VWF. Multimer analysis revealed that factor VIII preferentially accelerated the cleavage of high molecular weight (HMW) multimers. The ability of factor VIII to enhance VWF cleavage by ADAMTS13 was rapidly lost after pretreatment of factor VIII with thrombin (F2; 176930). Cao et al. (2008) concluded that factor VIII regulates proteolytic processing of VWF by ADAMTS13 under shear stress, which depends on the high-affinity interaction between factor VIII and VWF.
Using recombinant variants of ADAMTS13 and VWF for kinetic analysis, Gao et al. (2008) determined that segments between gln1624 and arg1668 in the VWF A2 domain interacted with the first thrombospondin-1 (see 188060) domain, the cys-rich domain, and the spacer domain of ADAMTS13. The individual interactions were relatively weak, but together they increased the rate of substrate cleavage. Internal deletion of gln1624 to arg1641 in the VWF A2 domain did not affect the cleavage rate, but short deletions on either side of the tyr1605-met1606 cleavage site abolished cleavage. Adding residues N-terminal to glu1554 in VWF reduced the rate of VWF cleavage by ADAMTS13.
Crystal Structure
Huizinga et al. (2002) presented the crystal structure of the platelet receptor glycoprotein 1B-alpha (GP1BA; 606672) amino-terminal domain and its complex with the VWF domain A1. In the complex, GP1BA wraps around one side of A1, providing 2 contact areas bridged by an area of solvated charge interaction. The structures explain the effects of gain-of-function mutations related to bleeding disorders and provide a model for shear-induced activation.
Zhou et al. (2011) determined the crystal structure of an engineered VWF A2 domain. The structure contained a Ca(2+)-binding site in the region (residues 1591 to 1602) connecting alpha-3 to beta-4. Mutation of asp1596 or asn1602 impaired the ability of the A2 domain to bind Ca(2+). Ca(2+) binding stabilized the A2 domain and impeded unfolding of the A2 domain, thereby protecting it from cleavage by ADAMTS13.
Sadler and Ginsburg (1993) reported on a database of polymorphisms in the VWF gene and pseudogene; Ginsburg and Sadler (1993) reported on a database of point mutations, insertions, and deletions.
Von Willebrand Disease Type 1
Eikenboom et al. (1996) described a family in the Netherlands in which 3 affected members with type 1 von Willebrand disease (193400) and VWF levels 10 to 15% of normal were heterozygous for a mutation in the VWF gene (C1149R; 613160.0028) The mutation resulted in a decrease in the secretion of coexpressed normal VWF, and the mutation was proposed to cause intracellular retention of pro-VWF heterodimers.
In affected members of 7 Italian families and in 1 German patient with von Willebrand disease 'Vicenza,' Schneppenheim et al. (2000) identified a heterozygous R1205H mutation in the VWF gene (613160.0027). Haplotype identity, with minor deviations in 1 Italian family, suggested a common but not very recent genetic origin of R1205H. The phenotype was characterized by these groups as showing autosomal dominant inheritance and low levels of VWF antigen in the presence of high molecular weight and ultra high molecular weight multimers, so-called 'supranormal' multimers, similar to those seen in normal plasma after infusion of desmopressin.
Von Willebrand Disease Type 2
In a patient with type 2 von Willebrand disease (613554), Bernardi et al. (1990) identified a heterozygous de novo deletion of a portion of the VWF gene containing at least codons 1147 through 1854. The VWF antigen (VWF:Ag) levels were one-fourth of normal, and ristocetin cofactor (VWF:RCo) activity was severely impaired. VWF morphology showed a reduction of high molecular weight multimers in plasma and platelets, consistent with type 2A VWD.
Iannuzzi et al. (1991) identified a heterozygous mutation in the VWF gene (613160.0001) in a patient with von Willebrand disease type 2A, which is characterized by a qualitative defect in VWF, resulting in the absence of large and intermediate VWF multimers, which may be caused by increased VWF proteolysis.
In 2 families with VWD, 1 with type 2B and another with type 1, Eikenboom et al. (1994) identified multiple consecutive nucleotide changes in the 5-prime end of exon 28 that resulted in sequences identical to the VWF pseudogene, although they were demonstrated to be in the active gene. Eikenboom et al. (1994) hypothesized that each of these multiple substitutions arose from a recombination event between the gene and pseudogene, rather than from single mutation events. The findings thus represented interchromosomal gene conversion involving chromosomes 12 and 22.
In affected members of 2 unrelated families with VWD type 2CB (see 613554), Riddell et al. (2009) identified 2 different heterozygous mutations in the collagen-binding A3 domain of the VWF gene (W1745C; 613160.0040 and S1783A; 613160.0042, respectively). The patients had clinically significant bleeding episodes. Laboratory studies showed normal values of VWF:RCo to VWF:Ag (RCo:Ag), normal VWF multimer analysis, and normal ristocetin-induced platelet aggregation, but markedly reduced ratios of VWF collagen-binding activity to VWF antigen (CB:Ag) against type III collagen and type I collagen. Treatment with DDAVP resulted in a good functional response with a rise in VWF:CB resulting from an overall increase in the amount of circulating VWF, even though the qualitative defect in collagen binding remained. These findings and in vitro expression studies indicated that these mutant proteins caused a specific defect in collagen binding, which Riddell et al. (2009) suggested represented a novel classification subtype termed 'VWF 2CB.'
A decreased VWF:RCo/VWF:Ag ratio implies a VWD type 2M defect that is characterized by decreased VWF-platelet interactions in the presence of normal multimer structure. Based on laboratory findings, Flood et al. (2010) observed an overrepresentation of VWD type 2M in African American individuals (80%) compared to Caucasians (30%), among all those categorized as having VWD type 2. In addition, most of the African American individuals had minimal bleeding symptoms despite a significantly reduced VWF:RCo/VWF:Ag ratio. Genetic analysis of 59 African American and 113 Caucasian controls identified a nonsynonymous SNP (asp1472-to-his; D1472H; rs1800383) in exon 28 in the A1 domain of the VWF gene that could fully explain the lower VWF:RCo/VWF:Ag ratios in African Americans (0.81) compared to Caucasians (0.94). Whereas 63% of the African Americans were positive for D1472H, only 17% of Caucasians had this SNP. Further analysis showed that the VWF 1472H allele fully accounted for the variation in VWF:RCo/VWF:Ag independent of race. In vitro studies showed that the D1472H substitution had no effect on VWF binding to platelet GP1BA in assays that did not use ristocetin, and did not alter VWF binding to collagen. Therefore, the VWF D1472H polymorphism causes substantial variation in VWF:RCo without altering the hemostatic function of VWF in vivo. Flood et al. (2010) concluded that polymorphisms in this region may affect the measurement of VWF activity by the ristocetin assay and may not reflect a functional defect or true hemorrhagic risk.
Schneppenheim et al. (2010) reported a high frequency (29%) of VWD type 2A subtype IIE among patients with type 2A studied in their laboratory. Subtype 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 3
In a patient with severe type 3 von Willebrand disease (277480), Peake et al. (1990) found a homozygous 2.3-kb deletion in the VWF gene which included exon 42; a novel 182-bp insert was found between the breakpoints. The patient had an alloantibody inhibitor to VWF. The insert was detected by PCR amplification both in the patient's DNA and in his carrier relatives.
In patients with VWD type 3, Zhang et al. (1992, 1992, 1992) identified homozygous or compound heterozygous mutations in the VWF gene (see, e.g., 613160.0015-613160.0017). Some heterozygous family members had a less severe phenotype, consistent with VWD type 1.
Denis et al. (1998) generated a mouse model for von Willebrand disease by using gene targeting. VWF-deficient mice appeared normal at birth; they were viable and fertile. Neither von Willebrand factor nor VWF-propolypeptide (von Willebrand antigen II) was detectable in plasma, platelets, or endothelial cells of the homozygous mutant mice. The mutant mice exhibited defects in hemostasis with a highly prolonged bleeding time and spontaneous bleeding events in approximately 10% of neonates. As in the human disease, the factor VIII level in these mice was reduced strongly as a result of the lack of protection provided by von Willebrand factor. Defective thrombosis in mutant mice was also evident in an in vivo model of vascular injury. In this model, the exteriorized mesentery was superfused with ferric chloride and the accumulation of fluorescently labeled platelets was observed by intravascular microscopy. Denis et al. (1998) concluded that these mice very closely mimic severe human von Willebrand disease.
Golder et al. (2010) generated transgenic mouse models of VWD type 2B by introducing mutations R1306W (613160.0005), V1316M (613160.0007), and R1341Q (613160.0008) into the murine Vwf gene. The mutant Vwf proteins were expressed by the liver and only present in the plasma compartment, not in platelets. Mutant mice showed variable thrombocytopenia, which was most severe in V1316M mice. Blood smears from mutant mice showed many platelet aggregates, which were not seen in wildtype mice, and plasma samples from mutant mice showed decreased numbers of Vwf multimers resulting from increased Adamts13-mediated proteolysis. Mice with the V1316M mutation also had large platelets. Even though the enhanced affinity of Vwf 2B mutant proteins to platelets could theoretically have a thrombotic effect, ferric chloride-induced injury to cremaster arterioles in mutant mice showed a marked reduction in thrombus development and platelet adhesion in the presence of circulating Vwf 2B.
Rayes et al. (2010) also generated mouse models of VWD type 2B by introducing the R1306Q and V1316M mutations in the murine Vwf gene. Both mutant proteins were associated with enhanced ristocetin-induced platelet aggregation, and mutant mice developed thrombocytopenia and circulating platelet aggregates, both of which were more pronounced for mice with the V1316M mutation. Only the V1316M mutant showed spontaneous platelet aggregation in vitro. Blood smears from mutant mice showed increased platelet size compared to wildtype. Both mutant proteins had a 2- to 3-fold reduced half-life and induced a 3- to 6-fold increase in number of giant platelets compared with wild-type Vwf. Loss of large multimers was observed in 50% of mutant mice. In vivo hemostatic potential of both mutants was severely impaired, even in an thrombotic model of arterial vessel occlusion. Mice who were doubly mutant for Vwf 2B and Adamts13 deficiency had more and larger circulating platelet aggregates and did not lack high molecular weight (HMW) multimers. The findings confirmed that VWD type 2B is dependent upon the type of mutation and pointed to an important role for ADAMTS13 in modulating platelet size as well as the removal of HMW VWF.
Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the mutation originally designated ILE865THR is now designated ILE1628THR (I1628T).
In affected members of a family with von Willebrand disease type 2A (see 613554), Iannuzzi et al. (1991) identified a 4883T-C transition in the VWF gene, resulting in an ile865-to-thr (I865T) substitution. Type 2A VWD is characterized by a qualitative defect in VWF, resulting in the absence of large and intermediate VWF multimers, which may be caused by increased VWF proteolysis. The I865T 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), 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 IIA 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 proteolytic cleavage site is located between tyr842 and met843.
Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the mutation originally designated ARG834TRP is now designated ARG1597TRP (R1597W).
In a patient with von Willebrand disease type 2A (see 613554), characterized by selective loss of high molecular weight VWF multimers, Ginsburg et al. (1989) identified a heterozygous 4789C-T transition in the VWF gene, resulting in an arg834-to-trp (R834W) substitution.
Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the mutation originally designated VAL844ASP is now designated VAL1607ASP (V1607D).
In a patient with von Willebrand disease type 2A (see 613554), characterized by selective loss of high molecular weight VWF multimers, Ginsburg et al. (1989) identified a heterozygous 4820T-A transversion in the VWF gene, resulting in a val844-to-asp (V844D) substitution.
Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the mutation originally designated TRP550CYS is now designated TRP1313CYS (W1313C).
In the patient identified as case 7 in the report by Kyrle et al. (1988) with laboratory findings consistent with the diagnosis of type 2B von Willebrand disease (see 613554), Ware et al. (1991) found a trp550-to-cys (W550C) substitution. The mutation is located in the domain of the molecule comprising residues 449 to 728 involved in the binding to platelet glycoprotein Ib-IX receptor complex (see 606672). This interaction is physiologically regulated so that it does not occur between circulating VWF and platelets but, rather, only at a site of vascular injury. The abnormal VWF found in type 2B von Willebrand disease has a characteristically increased affinity for GP Ib and binds to the circulating platelets.
Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the mutation originally designated ARG543TRP is now designated ARG1306TRP (R1306W).
In 2 unrelated patients with VWD type 2B (see 613554), Randi et al. (1991) identified a heterozygous 4166C-T transition in exon 28 of the VWF gene, resulting in an arg543-to-trp (R543W) substitution in the domain that interacts with platelet glycoprotein GP1BA (606672). Both patients had previously been reported by Ruggeri et al. (1980) as having VWD with a heightened interaction between platelets and VWF. Patient plasma showed a decrease in large VWF multimers due to spontaneous binding of VWF to platelets and subsequent clearance from the circulation.
Donner et al. (1992) studied 20 patients from 9 unrelated families with type 2B VWD from Denmark, Germany, and Sweden. Fifteen patients in 5 families were heterozygous for the R543W mutation. In 2 of the 5 families, it represented a de novo mutation. In one of the other families, the father, though asymptomatic and with normal laboratory test results, carried the mutation in heterozygous form.
Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the mutation originally designated ARG545CYS is now designated ARG1308CYS (R1308C).
In 7 patients from 4 unrelated families with VWD type 2B (see 613554), Randi et al. (1991) identified a heterozygous 4172C-T transition in exon 28 of the VWF gene, resulting in an arg545-to-cys (R545C) substitution in the domain that interacts with platelet glycoprotein GP1BA (606672). Patient plasma showed a decrease in large VWF multimers due to spontaneous binding of VWF to platelets and subsequent clearance from the circulation. Examination of the RFLP haplotype background for the R545C mutations identified in their study permitted Randi et al. (1991) to conclude that the mutation had occurred independently 3 times; a fourth patient represented a new mutation.
Donner et al. (1991) reported another family with this mutation. In a later study of 20 patients from 9 unrelated families with type 2B VWD from Denmark, Germany, and Sweden, Donner et al. (1992) found the arg545-to-cys mutation in heterozygous state in 4 affected persons in 3 families.
In a Japanese patient with VWD type 2B, Hagiwara et al. (1996) identified a homozygous mutation in exon 28 of the VWF gene, resulting in an arg1308-to-cys (R1308C) substitution.
Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the mutation originally designated VAL553MET is now designated VAL1316MET (V1316M).
In a patient with VWD type 2B (see 613554), Randi et al. (1991) identified a heterozygous 4196G-A transition in exon 28 of the VWF gene, resulting in a val553-to-met (V553M) substitution in the domain that interacts with platelet glycoprotein GP1BA (606672). Patient plasma showed a decrease in large VWF multimers due to spontaneous binding of VWF to platelets and subsequent clearance from the circulation.
Murray et al. (1992) also observed this mutation in multiple members of a family with type 2B von Willebrand disease. They showed by VWF polymorphism analysis that the mutation originated in a VWF gene transmitted from a phenotypically normal grandfather. Analysis of the sperm from this individual showed that approximately 5% of the germline contained the mutant sequence.
Jackson et al. (2009) identified a heterozygous V1316M substitution in affected members of a large French Canadian family with VWD type 2B that was described by Milton et al. (1984) as having the 'Montreal platelet syndrome.' Affected individuals had lifelong bruising; some patients had severe postoperative bleeding, postpartum hemorrhage, and gastrointestinal bleeding. A significant proportion of platelets occurred in microaggregates typically containing 2 to 6 platelets, and the aggregation could be increased by stirring. Affected family members had macrothrombocytopenia, borderline to normal VWF antigen, low ristocetin cofactor activity, and normal factor VIII coagulant activity, all consistent with VWD type 2B.
Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the mutation originally designated ARG578GLN is now designated ARG1341GLN (R1341Q).
In a patient with VWD type 2B (see 613554), Cooney et al. (1991) identified a heterozygous 4022G-A transition in the VWF gene, resulting in an arg578-to-gln (R578Q) substitution within the putative GP1BA (606672)-binding domain.
Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the mutation originally designated SER850PRO is now designated SER1613PRO (S1613P).
Randi et al. (1991) suggested that mutations causing type IIA von Willebrand disease are clustered in the A2 domain of the VWF gene. The ser850-to-pro (S850P) mutation, designated S1613P based on a different numbering system, is in the A2 region of the gene (Goodeve, 2010).
Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the polymorphism originally designated ARG636HIS is now designated ARG1399HIS (R1399H).
Cooney et al. (1991) found a rare sequence polymorphism at nucleotide 4196 of the VWF gene. A 4196G-A transition led to an arg636-to-his (R636H) substitution. The allele frequency was estimated to be about 0.015. Although the change was within the region involved in binding to platelet glycoprotein receptor and the region mutant in von Willebrand disease type 2B (see 613554), no hematologic abnormality was associated with the change.
Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the mutation originally designated THR28MET is now designated THR791MET (T791M).
In a 50-year-old French woman, born of consanguineous parents, with the Normandy type of VWD (VWD2N; see 613554) reported by Mazurier et al. (1990), Gaucher et al. (1991) identified a homozygous 791C-T transition in exon 18 of the VWF gene, resulting in a thr28-to-met (T28M) substitution in the mature VWF subunit. The woman had a lifelong history of excessive bleeding, and laboratory data showed decreased factor VIII (300841), subnormal bleeding time, and normal VWF multimers. VWF isolated from patient plasma was unable to bind factor VIII. Gaucher et al. (1991) noted that the phenotype resembled hemophilia A, or F8 deficiency, but showed autosomal recessive instead of X-linked inheritance.
By functional expression studies, Tuley et al. (1991) showed that the T28M mutation occurred in the factor VIII binding site of the VWF molecule. The corresponding mutant recombinant molecule formed normal multimers and had normal ristocetin cofactor activity, but had a defect in factor VIII binding.
Wise et al. (1993) reported a family with VWD type 2N ascertained through a female patient with low levels of factor VIII activity. The patient was homozygous for the thr28-to-met mutation, which was heterozygous in both parents.
Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the mutation originally designated ARG53TRP is now designated ARG816TRP (R816W).
In a family with the Normandy type of von Willebrand disease (VWD2N; see 613554), Gaucher et al. (1991) demonstrated homozygosity for a C-to-T transition resulting in an arg53-to-trp (R53W) substitution in the mature protein. Although there was no known parental consanguinity, both parents originated from the same village in Portugal. The 2 alleles showed sequence variation within the intron 40 VNTR and might have arisen after the arg53-to-trp mutation occurred.
Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the mutation originally designated ARG91GLN is now designated ARG854GLN (R854Q).
In a patient with the Normandy type of von Willebrand disease (VWD2N; see 613554), Gaucher et al. (1991) demonstrated compound heterozygosity for the arg53-to-trp mutation (193400.0012) and another C-to-T transition that resulted in a substitution of glutamine for arginine-91. The patient's parents were related as second cousins.
Hilbert et al. (2004) reported 2 unrelated French patients with type 2N VWD who were compound heterozygous for R854Q and another pathogenic mutation (Y795C, 613160.0031 and C804F, 613160.0032, respectively).
Peerlinck et al. (1992) identified a heterozygous A-to-G transition in exon 20 of the VWF gene, resulting in an arg854-to-gln (R854Q) substitution, in a 23-year-old woman with a lifelong history of bleeding and low VWF levels, consistent with von Willebrand disease type 1 (193400). Laboratory studies showed disproportionately low factor VIII (F8; 300841) and decreased binding capacity of VWF for F8. The R854Q substitution occurred in the putative factor VIII-binding domain. All VWF multimers were normal. Neither parent was clinically affected, but laboratory studies showed that the father had partially increased bleeding time and partially decreased VWF antigen. Restriction enzyme analysis indicated that the unaffected mother was also heterozygous for the R854Q mutation, and that the patient had inherited a hypomorphic 'silent' VWF allele from her father. Peerlinck et al. (1992) noted that the inheritance pattern in this family was difficult to determine, but concluded that the presence of the 'silent' allele allowed the clinical expression of the mutated second allele, resulting in a recessive phenotype in the proband. Peerlinck et al. (1992) commented that although the phenotype was similar to that of the 'Normandy' type 2N variant (see 613554), the patient also had quantitatively low VWF and was thus classified as having VWD type 1.
In a patient with von Willebrand disease type 3 (277480), Zhang et al. (1992) identified a homozygous C-to-T transition in exon 28 of the VWF gene, resulting in an arg1659-to-ter (R1659X) substitution. Both parents carried the heterozygous mutation; the clinical features of the family were not reported.
Zhang et al. (1992) identified the R1659X mutation in affected members of 3 families from western Finland with VWD type 3. Severely affected individuals were either homozygous or presumed to be compound heterozygous with another pathogenic mutation. In 1 family, heterozygous mutation carriers had a less severe phenotype, consistent with type 1 VWD (193400).
In a Swedish patient with VWD type 3 (277480) and pronounced bleeding tendency, Zhang et al. (1992) identified homozygous C-to-T transition in exon 32 of the VWF gene, resulting in an arg1852-to-ter (R1852X) substitution. Two additional Swedish patients with type 3 were heterozygous for the mutation, but were predicted to be compound heterozygous for another mutation because their phenotype was more severe than other family members, who had type 1 disease (193400).
In a patient with severe VMD type 3 (277480), Zhang et al. (1992) identified a C-to-T transition in exon 45 of the VWF gene, resulting in an arg2635-to-ter (R2635X) substitution. Although the patient was heterozygous for this mutation, he was thought to be a compound heterozygote for another, as yet unidentified mutation, since he had severe disease.
Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the mutation originally designated GLY561SER is now designated GLY1324SER (G1324S).
In a patient with VWD type 2M (see 613554), Rabinowitz et al. (1992) identified a heterozygous mutation in exon 28 of the VWF gene, resulting in a gly561-to-ser (G561S) substitution within the GP1BA (606672)-binding domain of the mature protein. Laboratory studies of patient plasma showed normal botrocetin-induced binding but no ristocetin-induced binding to platelet glycoprotein Ib. The patient's plasma VWF contained a full range of multimers. The mutant recombinant protein formed normal multimers, but exhibited the same functional defect as the patient's plasma VWF. The patient was originally described by Howard et al. (1984) and Andrews et al. (1989).
Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the mutation originally designated CYS509ARG is now designated CYS1272ARG (C1272R).
In a patient with type 2A von Willebrand disease (see 613554), Lavergne et al. (1992) found a 3814T-C transition in the 5-prime end of exon 28 of the VWF gene, resulting in a cys509-to-arg (C509R) substitution. This mutation eliminated an intramolecular disulfide bridge formed by cys509 and cys695. The bridge is important to maintenance of the configuration of VWF functional domains that interact with platelet glycoprotein Ib-IX. However, it appeared that this bridge also affects the processing and composition of VWF multimers, since the patient had a type 2A phenotype. The amino acid substitution was the result of a 381T-C transition. The findings suggested a broader pathogenic mechanism for VWF type 2A.
Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the mutation originally designated VAL551LEU is now designated VAL1314LEU (V1314L).
In 1 of 20 patients from 9 unrelated families with type 2B VWD (see 613554) from Denmark, Germany, and Sweden, Donner et al. (1992) found heterozygosity for a de novo val551-to-leu (V551L) mutation. In most of the patients with type 2B VWD, spontaneous thrombocytopenia had been recorded on at least one occasion. The patient with the val551-to-leu substitution and 5 patients with the arg543-to-trp (613160.0005) substitution had had bleeding associated with thrombocytopenia in the neonatal period or early infancy.
Among 24 patients with von Willebrand disease type 3 (277480), Zhang et al. (1992) found that 24 of the 48 chromosomes harbored a 1-bp deletion in a stretch of 6 cytosines at position 2679-2684 in exon 18 of the VWF gene. Nine patients were homozygous and 6 were heterozygous for the mutation. The deletion interrupted the reading frame and resulted in a translational stop codon at position V842 in the amino acid sequence. Translation of the mutant mRNA would yield only a severely truncated mature VWF (48 of 2,050 amino acids) after removal of the propeptide.
Zhang et al. (1993) demonstrated that deletion of 1 cytosine in exon 18 was the mutation in the Aland family (family S) in which the disease was first reported by von Willebrand (1926). They reported studies of descendants of the original family; only heterozygotes were found surviving. The proposita was a 5-year-old girl, who later bled to death during her fourth menstrual period. She had a normal coagulation time, but the bleeding time was prolonged, despite a normal platelet count. All but 1 of her 11 sibs had bleeding symptoms, as did both of her parents, who were third cousins, and many members of her family on both sides. Four of the proband's sisters had died of uncontrolled bleeding in early childhood; 3 died from gastrointestinal bleeding and 1 from bleeding after she bit her tongue in a fall. The predominant symptoms were bleeding from mucous membranes, such as from the nose, the gingivae after tooth extractions, the uterus, and the gastrointestinal tract. In contrast to hemophilia, hemarthroses seemed to be rare. All 5 of the girls who died from uncontrolled bleeding were probably homozygous for the deletion.
Mertes et al. (1993) found that the single cytosine deletion in exon 18 observed in half the alleles of 24 Swedish VWD type 3 patients (Zhang et al., 1992) occurred uncommonly in German patients with type 3 VWD; only 1 out of 24 alleles carried the delta-C mutation. A founder effect might explain the higher frequency in Sweden.
Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the mutation originally designated PHE751CYS is now designated PHE1514CYS (F1514C).
In 8 patients from a large type 2A (see 613554) von Willebrand disease family, Gaucher et al. (1993) found a heterozygous T-to-G transversion resulting in a phe751-to-cys (F751C) substitution in the mature subunit. Type 2A is a variant form of von Willebrand disease characterized by the absence of high molecular weight VWF multimers in plasma. Gaucher et al. (1993) noted that most of the candidate missense mutations potentially responsible for type 2A VWD have been found clustered within a short segment of VWF, lying between gly742 and glu875 of the mature subunit. Gaucher et al. (1993) suggested that the mutation may induce a conformational change of the VWF subunit affecting either its sensitivity to proteolytic cleavage or, more likely, its intracellular transport as suggested by the abnormal multimeric pattern of platelet VWF observed in these patients.
In a German woman with von Willebrand disease type 2 (613554), referred to as type IIC, Schneppenheim et al. (1995) identified a homozygous 1898G-A transition in exon 14 of the VWF gene, resulting in a gly550-to-arg (G550R) substitution in the D2 domain. The proband had frequent epistaxis, easy bruising, and menorrhagia, and laboratory studies showed decreased VWF activity and decreased levels of high molecular weight multimers. The subtype of VWD was originally referred to as 'type IIC,' which shows recessive inheritance and an altered multimer pattern. Further family members were heterozygous for the mutation and were phenotypically normal or only mildly affected, in accordance with the recessive pattern of inheritance.
Sadler et al. (2006) stated that the subtype previously known as VWD IIC is due to mutations in the VWF propeptide that prevent multimerization of VWF in the Golgi apparatus. This form is now referred to as VWD type 2A.
Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the mutation originally designated CYS2010ARG is now designated CYS2773ARG (C2773R).
In 2 unrelated patients with VWD type 2 (613554), Schneppenheim et al. (1996) identified a heterozygous cys2010-to-arg (C2010R) mutation in the mature VWF protein. Recombinant expression of mutant VWF fragments demonstrated that the mutation was responsible for defective disulfide bonding of the C-terminal domains, thus impairing dimer formation. In 1 family, both alleles were normal in the parents and 1 sister; thus, the mutation originated de novo in the proposita. The phenotype of what was then called type IID von Willebrand disease includes autosomal dominant inheritance of a moderate to severe hemorrhagic diathesis, prolonged bleeding time, normal factor VIII procoagulant and VWF antigen levels, but markedly reduced ristocetin cofactor activity due to the lack of large VWF multimers in plasma.
Sadler et al. (2006) stated that the subtype previously known as VWD IID is due to heterozygous mutations in the C-terminal domain of VWF that prevent VWF dimerization in the endoplasmic reticulum. This form is now referred to as VWD type 2A.
Holmberg et al. (1998) found that a patient with type 2 VWD (613554) reported by Ruggeri et al. (1982) was compound heterozygous for 2 mutations in the VWF gene: a null mutation and a 6-nucleotide insertion, 1212ins6 (AATCCC), in exon 11, predicting the insertion of the amino acids asparagine and proline between phenylalanine-404 and threonine-405 of the von Willebrand propeptide. The patient was originally classified as type IIC, since laboratory studies showed absence of the high molecular weight multimers and a marked increase of the smallest multimer (the protomer) in both plasma and platelets. The IIC phenotype showed recessive inheritance.
Sadler et al. (2006) stated that the subtype previously known as VWD IIC is due to mutations in the VWF propeptide that prevent multimerization of VWF in the Golgi apparatus. This form is now referred to as VWD type 2A.
The arg1205-to-his mutation (R1205H) in the VWF gene is sometimes referred to as VWF Vicenza.
In affected members of 7 Italian families and in 1 German patient with von Willebrand disease (193400) 'Vicenza,' Schneppenheim et al. (2000) identified a heterozygous 3864G-A transition in exon 27 of the VWF gene, resulting in an R1205H substitution in the D3 domain. The mutation was not found in unaffected family members or in 100 control chromosomes. Haplotype identity, with minor deviations in 1 Italian family, suggested a common but not very recent genetic origin of R1205H. Von Willebrand disease 'Vicenza' was originally described in patients living in the region of Vicenza in Italy (Mannucci et al., 1988). Randi et al. (1993) demonstrated that the clinical disorder in Italian patients is linked to the VWF gene. A number of additional families were identified in Germany by Zieger et al. (1997). The phenotype was characterized by these groups as showing autosomal dominant inheritance and low levels of VWF antigen in the presence of high molecular weight and ultra high molecular weight multimers, so-called 'supranormal' multimers, similar to those seen in normal plasma after infusion of desmopressin.
Casonato et al. (2002) identified 4 additional families with the R1205H variant. Affected individuals showed a mild bleeding tendency and significant decrease in plasma VWF antigen and ristocetin cofactor activity, but normal platelet VWF levels. Larger than normal VWF multimers were also observed. However, VWF multimers disappeared rapidly from the circulation after desmopressin, indicating reduced survival of the mutant VWF protein. Since ristocetin-induced platelet aggregation was normal, Casonato et al. (2002) attributed the phenotype to reduced survival of normally synthesized VWF, which is consistent with type 1 VWF.
In Wales, Lester et al. (2006) investigated 7 kindreds with VWD Vicenza R1205H. All affected individuals had been diagnosed with moderate to severe type 1 VWD. Among all families with highly penetrant type 1 VWD investigated in the center, heterozygosity for the R1205H mutation was found to be the most common underlying defect. A severe laboratory phenotype associated with a bleeding history that was milder than expected was commonly observed. Lester et al. (2006) provided evidence that the R1205H mutation can arise de novo.
Cumming et al. (2006) identified the Vicenza variant in 4 (12.5%) of 32 UK patients with type 1 VWD. These authors stated that the R1205H substitution resulted from a 3614G-A transition in exon 27. The mutation was highly penetrant and consistently associated with moderate to severe type I disease. VWF multimer studies did not show the presence of ultralarge multimers in any affected individuals; the authors thus classified the Vicenza variant to be a type 1 quantitative defect, rather than a type 2M qualitative defect as had been suggested by Castaman et al. (2002). Three of the 4 families reported by Cumming et al. (2006) shared the same haplotype, suggesting a common origin of the mutation.
In a review, Sadler et al. (2006) noted that the Vicenza VWF variant has increased clearance compared to wildtype VWF. Sadler et al. (2006) also noted that the Vicenza variant has been classified as VWD type 2M due to the presence of high molecular weight multimers. However, since VWF antigen and functional activity are decreased proportionately, it is better classified as VWD type 1.
Eikenboom et al. (1996) described a family in the Netherlands in which 3 affected members with type 1 von Willebrand disease (193400) and VWF levels 10 to 15% of normal were heterozygous for a mutation in exon 26 of the VWF gene, resulting in a cys1149-to-arg (C1149R) substitution in the D3 domain (numbered from the initiation codon, or cys386-to-arg, numbered from the N terminus of the mature subunit). The mutation resulted in a decrease in the secretion of coexpressed normal VWF, and the mutation was proposed to cause intracellular retention of pro-VWF heterodimers. The multimer pattern remained nearly normal and consistent with a dominant VWD type 1 phenotype.
Bodo et al. (2001) performed experiments supporting the hypothesis that normal and C1149R mutant subunits formed heterodimers that, like homodimers of C1149R, were retained in the endoplasmic reticulum. Such a mechanism would explain the dominant-negative effect of the C1149R mutation on VWF secretion, and the authors suggested that a similar dominant-negative mechanism could cause quantitative deficiencies of other multisubunit proteins.
O'Brien et al. (2003) addressed the molecular basis of type 1 von Willebrand disease (193400) in a comprehensive manner through a Canadian population-based study. In 10 Canadian families and 2 families from the UK with type 1 VWD, O'Brien et al. (2003) identified a heterozygous 4751A-G transition in exon 28 of the VWF gene, resulting in a tyr1584-to-cys (Y1584C) substitution. The Y1584C variant was found in 1 of 100 controls, but this individual had low VWF antigen levels, suggesting an affected status. One study participant with the mutation had a normal VWF antigen level and no history of bleeding, suggesting incomplete penetrance, and another who was homozygous for the mutation had significantly decreased VWF antigen levels. The mutation was associated with a common haplotype in a significant portion of patients with the disorder and was in-phase with a splice site variation (5312-19A-C) in some families. In vitro functional expression studies showed that the mutation resulted in increased intracellular retention of the VWF protein, resulting in a quantitative defect. Molecular dynamic simulation on a homology model of the VWF-A2 domain containing the Y1584C mutation showed that no significant structural changes occurred as a result of the substitution, but that a new solvent-exposed reactive thiol group was apparent.
Bowen and Collins (2004) described a patient with type 1 von Willebrand disease in whom the von Willebrand factor showed increased susceptibility to proteolysis by ADAMTS13 (604134). Investigation of additional family members indicated that increased susceptibility was heritable, but it did not track uniquely with type 1 VWD. Sequence analysis showed that increased susceptibility to proteolysis tracked with the Y1584C substitution. A prospective study of 200 individuals yielded 2 Y1584C heterozygotes; for both, plasma VWF showed increased susceptibility to proteolysis.
Bowen et al. (2005) identified heterozygosity for the Y1584C variant in 19 (25%) of 76 UK patients with type 1 VWD. This corresponded to 8 (27%) of 30 total families studied. However, the Y1584C variant did not segregate with disease in 4 families: 5 unaffected individuals carried the variant, whereas 3 affected individuals did not. These findings indicated that Y1584C is not solely causative of type 1 VWD. Eighteen of the 19 patients were ABO blood group (616093) type O, suggesting there may be an interaction between C1584 and blood group O. In vitro studies of plasma showed that Y1584C VWF had increased susceptibility to proteolysis by ADAMTS13, even in those who did not have VWD. Bowen et al. (2005) proposed a mechanism in which Y1584C VWF undergoes increased proteolysis, which may increase bleeding risk in carriers. However, presence for the variant is not causative for the disorder, and may instead represent a risk factor.
Cumming et al. (2006) identified heterozygosity for the Y1584C variant in 8 (25%) of 32 UK families and in 19 (17%) of 119 related individuals with type 1 VWD. Eighteen (95%) of the 19 individuals were blood group O. Heterozygosity for Y1584C segregated with VWD in 3 families, did not segregate with VWD in 4 families, and showed equivocal results in 2 families. Cumming et al. (2006) concluded that Y1594C is a polymorphism that is frequently associated with type 1 VWD, but shows incomplete penetrance and does not consistently segregate with the disease. The association with blood group type O may be related to the fact that both blood group O and Y1584C are associated with increased proteolysis of VWF by ADAMTS13.
In a French mother and son with VWD type 2M (see 613554), Stepanian et al. (2003) identified a heterozygous 3854C-T transition in exon 28 of the VWF gene, resulting in a ser1285-to-phe (S1285F) substitution in the A1 loop of the protein. In vitro functional expression studies in COS-7 cells showed that the mutant VWF had markedly reduced ristocetin-induced binding to platelets via GP1BA (606672), consistent with a loss of function. The findings indicated that the S1285F mutation altered the folding of the A1 loop and prevented the correct exposure of VWF binding sites to GP1BA. Both patients had a moderate bleeding syndrome with epistaxis and easy bruising. Laboratory studies showed mildly decreased VWF antigen levels, normal multimers, and severely decreased VWF functional activity. Factor VIII (F8; 300841) was mildly decreased and platelet counts were normal.
In a French patient with VWD type 2N (see 613554), Hilbert et al. (2004) identified compound heterozygosity for 2 mutations in the VWF gene: a 2384A-G transition in exon 18 resulting in a tyr795-to-cys (Y795C) substitution in the D-prime domain, and R854Q (613160.0013). In vitro functional expression assays showed that the mutant VWF protein had decreased binding to factor VIII (300841), and resulted in an abnormal multimeric pattern consistent with ultralarge multimers. Hilbert et al. (2004) suggested that the effect on the cysteine residue may alter protein conformation.
In a French patient with VWD type 2N (see 613554), Hilbert et al. (2004) identified compound heterozygosity for 2 mutations in the VWF gene: a 2411G-T transversion in exon 18 resulting in a cys804-to-phe (C804F) substitution in the D-prime domain, and R854Q (613160.0013). In vitro functional expression assays showed that the mutant VWF protein had decreased binding to factor VIII (300841), and resulted in an abnormal multimeric pattern consistent with loss of ultralarge multimers. Hilbert et al. (2004) suggested that the effect on the cysteine residue may alter protein conformation.
Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the mutation originally designated PRO503LEU is now designated PRO1266LEU (P1266L).
In affected members of a Swedish family (Holmberg et al., 1986) and a German family with a variant of VWD type 2B (see 613554), Holmberg et al. (1993) identified a heterozygous C-to-T transition in the VWF gene, resulting in a pro503-to-leu (P503L) substitution in the mature subunit. 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. The bleeding time was variously prolonged, and VWF:Ag, VWF activity, and F8 were decreased. All VWF multimers were present, and there was no thrombocytopenia. The defect in this family, inherited as an autosomal dominant trait, resembled that of type 2B because of the response to ristocetin, but differed because all VWF multimers were present. Holmberg et al. (1986) referred to it as 'type 2 Malmo.' Weiss and Sussman (1985) reported a similarly affected family, and referred to this variant as 'type I New York' (Sadler et al., 2006). Wylie et al. (1988) also described this variant and noted that there was no spontaneous aggregation of platelets.
Sadler et al. (2006) emphasized that this variant is a form of VWD type 2B with increased sensitivity to ristocetin in vivo.
In several patients from northern Italy with VWD type 3 (277480), Eikenboom et al. (1998) identified a homozygous mutation in the VWF gene, resulting in a cys2362-to-phe (C2362F) substitution. Haplotype analysis indicated a founder effect.
Tjernberg et al. (2006) demonstrated that recombinant C2362F expressed in 293T human kidney cells resulted in significantly decreased expression of the mutant protein (8% of controls), although there was similar production. The findings indicated increased intracellular retention of the mutant protein. The mutant protein produced showed less of the multimeric structure, suggesting that the loss of a cysteine on an interchain bond impaired normal multimerization, since there was no difference in subunit size from the wildtype. There was also no evidence of a dominant-negative effect, suggesting that the ultimate effects of the C2362F mutation were similar to that of a null allele.
In a 20-year-old French woman with VWD type 2N (see 613554), Mazurier et al. (2002) identified compound heterozygosity for 2 mutations in the VWF gene: a 1071C-A transversion in exon 9, resulting in a tyr357-to-ter (Y357X) substitution, and a 3178T-C transition in exon 24, resulting in a cys1060-to-arg (C1060R; 613160.0036) substitution. The authors noted that the Y357X mutation is a type 3 mutation (277480) presumably because it represents a truncating mutation and lack of protein expression. The patient had very low levels of VWF and F8, and absent binding of VWF to F8. She had 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).
See 613160.0035 and Mazurier et al. (2002).
In 3 Turkish boys, born of consanguineous parents, with VWD type 2A (see 613554), Haberichter et al. (2010) identified a homozygous 1583A-G transition in exon 14 of the VWF gene, resulting in an asn528-to-ser (N528S) substitution in the D2 domain of the propeptide. The phenotype was characterized by significant mucocutaneous bleeding beginning in childhood; 1 patient had joint bleeding. The patients had decreased plasma and platelet VWF antigen and decreased platelet VWF binding to collagen, with only slightly reduced F8 activity. There was a poor VWF response to desmopressin infusion, indicating lack of VWF storage in endothelial cells. The VWF multimer pattern lacked both high molecular weight multimers and medium-sized multimers particularly severe in platelets, consistent with VWD type 2A and the historical subclassification of type IIC. In vitro functional expression studies in mammalian cells showed that the N528S mutation introduced into a full-length VWF expression vector resulted in decreased VWF secretion (7.5% of controls) with an abnormal multimer pattern lacking both high molecular weight and medium-sized multimers, and lack of proper trafficking to storage granules. Detailed studies using coexpression of the mutant and wildtype propeptide with mutant and wildtype full-length VWF indicated a defective interaction of VWF with its intracellular propeptide chaperone, resulting in loss of regulated storage of VWF. Heterozygous expression of the mutant and wildtype alleles resulted in normal VWF secretion and multimerization, confirming the recessive nature of this mutation.
In 3 Caucasian British patients, including 2 sibs, with VWD type 3 (277480), Sutherland et al. (2009) identified a homozygous 8,631-bp deletion in the VWF gene, resulting in an in-frame deletion of exons 4 and 5. The deletion spanned from within intron 3 to within intron 5, and the breakpoints occurred in inverted AluY repeat elements. Analysis of other patients with VWD type 3 showed that 4 were compound heterozygous for the exon 4-5 deletion and another pathogenic mutation, and 1 was heterozygous for the deletion but with no second mutation detected. In total, 7 of 12 white patients with VWD type 3 carried this deletion, which was not found in 9 patients of Asian origin. Haplotype analysis confirmed a founder effect in the white British population. Heterozygosity for this deletion was found in 2 of 34 probands with VWD type 1 (193400), their affected family members, and 1 unaffected family member, indicating reduced penetrance. An unrelated patient with VWD type 1 was also found to carry a heterozygous deletion. In vitro functional expression studies showed that the deletion resulted in significantly decreased protein secretion, with a 98% decrease in the homozygous state and an 86% decrease in the heterozygous state, consistent with a dominant-negative effect. Expression of the homozygous mutation, but not of the heterozygous mutation, resulted in defective multimer production. The mutation was not found in 200 control alleles.
In 12 (32%) of 38 probands with von Willebrand disease type 2A/IIE (see 613554), Schneppenheim et al. (2010) identified a heterozygous 3437A-C transversion in exon 26 of the VWF gene, resulting in a tyr1146-to-cys (Y1146C) substitution in the D3 domain. Plasma from patients showed complete absence of large VWF multimers, and in vitro expression studies indicated that the Y1146C-mutant protein caused a severe reduction in or lack of high molecular weight 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 several mechanisms acting in concert, including decreased secretion of VWF, the change affecting 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 primary factor.
In an elderly woman with von Willebrand disease type 2CB (see 613554), Riddell et al. (2009) identified compound heterozygosity for 2 mutations in the VWF gene: a 5235G-T transversion in exon 30, resulting in a trp1745-to-cys (W1745C) substitution in the A3 domain, and R760H (613160.0041). She had a lifelong history of severe bleeding episodes, including epistaxis, ecchymosis, menorrhagia, and bleeding after dental extractions. The proband had 2 offspring, each of whom was heterozygous for 1 of the mutations and showed minor bleeding symptoms not requiring treatment. Both persons with the W1745C mutation had markedly reduced ratios of VWF collagen-binding activity to VWF antigen (CB:Ag) against type III collagen and type I collagen. There were normal values of VWF:RCo to VWF:Ag (RCo:Ag), normal VWF multimer analysis, and normal ristocetin-induced platelet aggregation. Treatment of the mother with DDAVP resulted in a good functional response with a rise in VWF:CB resulting from an overall increase in the amount of circulating VWF, even though the qualitative defect in collagen binding remained. These findings and in vitro expression studies indicated that the W1745C-mutant protein caused a specific defect in collagen binding, which Riddell et al. (2009) suggested represented a novel classification subtype termed 'VWF 2CB.'
In a patient with a mild bleeding tendency and laboratory studies consistent with VWD type 1 (193400), Riddell et al. (2009) identified a heterozygous 2279G-A transition in the VWF gene, resulting in an arg760-to-his (R760H; 613160.0041) substitution. Laboratory studies showed a concordant reduction in VWF:Ag, VWF:RCo, and VWF:CB, with a normal multimer pattern.
In a mother and son with VWD type 2CB (see 613554), Riddell et al. (2009) identified a heterozygous 5347T-G transversion in exon 31 of the VWF gene, resulting in a ser1783-to-ala (S1783A) substitution in the A3 domain. Laboratory studies showed normal VWF:Ag, VWF:RCo, and multimers, but decreased binding to both collagen I and collagen III. Defective collagen binding was confirmed by in vitro expression studies. Treatment with DDAVP resulted in a good functional response with a rise in VWF:CB resulting from an overall increase in the amount of circulating VWF, even though the qualitative defect in collagen binding remained. These findings indicated that the S1783A-mutant protein caused a specific defect in collagen binding, which Riddell et al. (2009) suggested represented a novel classification subtype termed 'VWF 2CB.'
Andrews, R. K., Booth, W. J., Gorman, J. J., Castaldi, P. A., Berndt, M. C. Purification of botrocetin from Bothrops jararaca venom: analysis of the botrocetin-mediated interaction between von Willebrand factor and the human platelet membrane glycoprotein Ib-IX complex. Biochemistry 28: 8317-8326, 1989. [PubMed: 2557900] [Full Text: https://doi.org/10.1021/bi00447a009]
Bahou, W. F., Bowie, E. J. W., Fass, D. N., Ginsburg, D. Molecular genetic analysis of porcine von Willebrand disease: tight linkage to the von Willebrand factor locus. Blood 72: 308-313, 1988. [PubMed: 2898953]
Barrow, L. L., Simin, K., Mohlke, K., Nichols, W. C., Ginsburg, D., Meisler, M. H. Conserved linkage of neurotrophin-3 and von Willebrand factor on mouse chromosome 6. Mammalian Genome 4: 343-345, 1993. [PubMed: 8318738] [Full Text: https://doi.org/10.1007/BF00357095]
Bernardi, F., Marchetti, G., Guerra, S., Casonato, A., Gemmati, D., Patracchini, P., Ballerini, G., Conconi, F. A de novo and heterozygous gene deletion causing a variant of von Willebrand disease. Blood 75: 677-683, 1990. [PubMed: 1967540]
Bodo, I., Katsumi, A., Tuley, E. A., Eikenboom, J. C. J., Dong, Z., Sadler, J. E. Type 1 von Willebrand disease mutation cys1149-to-arg causes intracellular retention and degradation of heterodimers: a possible general mechanism for dominant mutations of oligomeric proteins. Blood 98: 2973-2979, 2001. [PubMed: 11698279] [Full Text: https://doi.org/10.1182/blood.v98.10.2973]
Bonthron, D., Orr, E. C., Mitsock, L. M., Ginsburg, D., Handin, R. I., Orkin, S. H. Nucleotide sequence of pre-pro-von Willebrand factor cDNA. Nucleic Acids Res. 14: 7125-7127, 1986. [PubMed: 3489923] [Full Text: https://doi.org/10.1093/nar/14.17.7125]
Bonthron, D. T., Handin, R. I., Kaufman, R. J., Wasley, L. C., Orr, E. C., Mitsock, L. M., Ewenstein, B., Loscalzo, J., Ginsburg, D., Orkin, S. H. Structure of pre-pro-von Willebrand factor and its expression in heterologous cells. Nature 324: 270-273, 1986. [PubMed: 3491324] [Full Text: https://doi.org/10.1038/324270a0]
Bowen, D. J., Collins, P. W., Lester, W., Cumming, A. M., Keeney, S., Grundy, P., Enayat, S. M., Bolton-Maggs, P. H. B., Keeling, D. M., Khair, K., Tait, R. C., Wilde, J. T., Pasi, K. J., Hill, F. G. The prevalence of the cysteine 1584 variant of von Willebrand factor is increased in type 1 von Willebrand disease: co-segregation with increased susceptibility to ADAMTS13 proteolysis but not clinical phenotype. Brit. J. Haemat. 128: 830-836, 2005. [PubMed: 15755288] [Full Text: https://doi.org/10.1111/j.1365-2141.2005.05375.x]
Bowen, D. J., Collins, P. W. An amino acid polymorphism in von Willebrand factor correlates with increased susceptibility to proteolysis by ADAMTS13. Blood 103: 941-947, 2004. [PubMed: 14525793] [Full Text: https://doi.org/10.1182/blood-2003-05-1505]
Cao, W., Krishnaswamy, S., Camire, R. M., Lenting, P. J., Zheng, X. L. Factor VIII accelerates proteolytic cleavage of von Willebrand factor by ADAMTS13. Proc. Nat. Acad. Sci. 105: 7416-7421, 2008. [PubMed: 18492805] [Full Text: https://doi.org/10.1073/pnas.0801735105]
Casonato, A., Pontara, E., Sartorello, F., Cattini, M. G., Sartori, M. T., Padrini, R., Girolami, A. Reduced von Willebrand factor survival in type Vicenza von Willebrand disease. Blood 99: 180-184, 2002. [PubMed: 11756169] [Full Text: https://doi.org/10.1182/blood.v99.1.180]
Castaman, G., Eikenboom, J. C. J., Bertina, R. M., Rodeghiero, F. Inconsistency of association between type 1 von Willebrand disease phenotype and genotype in families identified in an epidemiological investigation. Thromb. Haemost. 82: 1065-1070, 1999. [PubMed: 10494765]
Castaman, G., Rodeghiero, F., Mannucci, P. M. The elusive pathogenesis of von Willebrand disease Vicenza. (Letter) Blood 99: 4243-4244, 2002. [PubMed: 12043692] [Full Text: https://doi.org/10.1182/blood.v99.11.4243]
Collins, C. J., Underdahl, J. P., Levene, R. B., Ravera, C. P., Morin, M. J., Dombalagian, M. J., Ricca, G., Livingston, D. M., Lynch, D. C. Molecular cloning of the human gene for von Willebrand factor and identification of the transcription initiation site. Proc. Nat. Acad. Sci. 84: 4393-4397, 1987. [PubMed: 3496594] [Full Text: https://doi.org/10.1073/pnas.84.13.4393]
Cooney, K. A., Nichols, W. C., Bruck, M. E., Bahou, W. F., Shapiro, A. D., Bowie, E. J. W., Gralnick, H. R., Ginsburg, D. The molecular defect in type IIB von Willebrand disease: identification of four potential missense mutations within the putative GpIb binding domain. J. Clin. Invest. 87: 1227-1233, 1991. [PubMed: 1672694] [Full Text: https://doi.org/10.1172/JCI115123]
Cumming, A., Grundy, P., Keeney, S., Lester, W., Enayat, S., Guilliatt, A., Bowen, D., Pasi, J., Keeling, D., Hill, F., Bolton-Maggs, P. H., Hay, C., Collins, P. B. An investigation of the von Willebrand factor genotype in UK patients diagnosed to have type 1 von Willebrand disease. Thromb. Haemost. 96: 630-641, 2006. [PubMed: 17080221]
Cumming, A. M., Armstrong, J. G., Pendry, K., Burn, A. M., Wensley, R. T. Polymerase chain reaction amplification of two polymorphic simple repeat sequences within the von Willebrand factor gene: application to family studies in von Willebrand disease. Hum. Genet. 89: 194-198, 1992. [PubMed: 1587530] [Full Text: https://doi.org/10.1007/BF00217122]
Denis, C., Methia, N., Frenette, P. S., Rayburn, H., Ullman-Cullere, M., Hynes, R. O., Wagner, D. D. A mouse model of severe von Willebrand disease: defects in hemostasis and thrombosis. Proc. Nat. Acad. Sci. 95: 9524-9529, 1998. [PubMed: 9689113] [Full Text: https://doi.org/10.1073/pnas.95.16.9524]
Dent, J. A., Berkowitz, S. D., Ware, J., Kasper, C. K., Ruggeri, Z. M. Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in type IIA von Willebrand factor. Proc. Nat. Acad. Sci. 87: 6306-6310, 1990. Note: Erratum: Proc. Nat. Acad. Sci. 87: 9508 only, 1990. [PubMed: 2385594] [Full Text: https://doi.org/10.1073/pnas.87.16.6306]
Donner, M., Andersson, A.-M., Kristoffersson, A.-C., Nilsson, I. M., Dahlback, B., Holmberg, L. An arg545-to-cys substitution mutation of the von Willebrand factor in type IIB von Willebrand's disease. Europ. J. Haemat. 47: 342-345, 1991. [PubMed: 1761120] [Full Text: https://doi.org/10.1111/j.1600-0609.1991.tb01858.x]
Donner, M., Kristoffersson, A. C., Lenk, H., Scheibel, E., Dahlback, B., Nilsson, I. M., Holmberg, L. Type IIB von Willebrand's disease: gene mutations and clinical presentation in nine families from Denmark, Germany and Sweden. Brit. J. Haemat. 82: 58-65, 1992. [PubMed: 1419803] [Full Text: https://doi.org/10.1111/j.1365-2141.1992.tb04594.x]
Eikenboom, J. C. J., Castaman, G., Vos, H. L., Bertina, R. M., Rodeghiero, F. Characterization of the genetic defects in recessive type 1 and type 3 von Willebrand disease patients of Italian origin. Thromb. Haemost. 79: 709-717, 1998. [PubMed: 9569178]
Eikenboom, J. C. J., Matsushita, T., Reitsma, P. H., Tuley, E. A., Castaman, G., Briet, E., Sadler, J. E. Dominant type 1 von Willebrand disease caused by mutated cysteine residues in the D3 domain of von Willebrand factor. Blood 88: 2433-2441, 1996. [PubMed: 8839833]
Eikenboom, J. C. J., Vink, T., Briet, E., Sixma, J. J., Reitsma, P. H. Multiple substitutions in the von Willebrand factor gene that mimic the pseudogene sequence. Proc. Nat. Acad. Sci. 91: 2221-2224, 1994. [PubMed: 8134377] [Full Text: https://doi.org/10.1073/pnas.91.6.2221]
Fay, P. J., Kawai, Y., Wagner, D. D., Ginsburg, D., Bonthron, D., Ohlsson-Wilhelm, B. M., Chavin, S. I., Abraham, G. N., Handin, R. I., Orkin, S. H., Montgomery, R. R., Marder, V. J. Propolypeptide of von Willebrand factor circulates in blood and is identical to von Willebrand antigen II. Science 232: 995-998, 1986. [PubMed: 3486471] [Full Text: https://doi.org/10.1126/science.3486471]
Flood, V. H., Gill, J. C., Morateck, P. A., Christopherson, P. A., Friedman, K. D., Haberichter, S. L., Branchford, B. R., Hoffmann, R. G., Abshire, T. C., Di Paola, J. A., Hoots, W. K, Leissinger, C., Lusher, J. M., Ragni, M. V., Shapiro, A. D., Montgomery, R. R. :Common VWF exon 28 polymorphisms in African Americans affecting the VWF activity assay by ristocetin cofactor. Blood 116: 280-286, 2010. [PubMed: 20231421] [Full Text: https://doi.org/10.1182/blood-2009-10-249102]
Gao, W., Anderson, P. J., Sadler, J. E. Extensive contacts between ADAMTS13 exosites and von Willebrand factor domain A2 contribute to substrate specificity. Blood 112: 1713-1719, 2008. [PubMed: 18492952] [Full Text: https://doi.org/10.1182/blood-2008-04-148759]
Gaucher, C., Hanss, M., Dechavanne, M., Mazurier, C. Substitution of cysteine for phenylalanine 751 in mature von Willebrand factor is a novel candidate mutation in a family with type IIA von Willebrand disease. Brit. J. Haemat. 83: 94-99, 1993. [PubMed: 8435341] [Full Text: https://doi.org/10.1111/j.1365-2141.1993.tb04637.x]
Gaucher, C., Jorieux, S., Mercier, B., Oufkir, D., Mazurier, C. The 'Normandy' variant of von Willebrand disease: characterization of a point mutation in the von Willebrand factor gene. Blood 77: 1937-1941, 1991. [PubMed: 2018834]
Gaucher, C., Mercier, B., Jorieux, S., Oufkir, D., Mazurier, C. Identification of two point mutations in the von Willebrand factor gene of three families with the 'Normandy' variant of von Willebrand disease. Brit. J. Haemat. 78: 506-514, 1991. [PubMed: 1832934] [Full Text: https://doi.org/10.1111/j.1365-2141.1991.tb04480.x]
Ginsburg, D., Handin, R. I., Bonthron, D. T., Donlon, T. A., Bruns, G. A. P., Latt, S. A., Orkin, S. H. Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization. Science 228: 1401-1406, 1985. [PubMed: 3874428] [Full Text: https://doi.org/10.1126/science.3874428]
Ginsburg, D., Konkle, B. A., Gill, J. C., Montgomery, R. R., Bockenstedt, P. L., Johnson, T. A., Yang, A. Y. Molecular basis of human von Willebrand disease: analysis of platelet von Willebrand factor mRNA. Proc. Nat. Acad. Sci. 86: 3723-3727, 1989. [PubMed: 2786201] [Full Text: https://doi.org/10.1073/pnas.86.10.3723]
Ginsburg, D., Sadler, J. E. Von Willebrand disease: a database of point mutations, insertions, and deletions. Thromb. Haemost. 69: 177-184, 1993. [PubMed: 8456431]
Ginsburg, D. Molecular genetics of von Willebrand disease. Thromb. Haemost. 82: 585-591, 1999. [PubMed: 10605755]
Golder, M., Pruss, C. M., Hegadorn, C., Mewburn, J., Laverty, K., Sponagle, K., Lillicrap, D. Mutation-specific hemostatic variability in mice expressing common type 2B von Willebrand disease substitutions. Blood 115: 4862-4869, 2010. [PubMed: 20371742] [Full Text: https://doi.org/10.1182/blood-2009-11-253120]
Goodeve, A. C. The genetic basis of von Willebrand disease. Blood Rev. 24: 123-134, 2010. [PubMed: 20409624] [Full Text: https://doi.org/10.1016/j.blre.2010.03.003]
Haberichter, S. L., Budde, U., Obser, T., Schneppenheim, S., Wermes, C., Schneppenheim, R. The mutation N528S in the von Willebrand factor (VWF) propeptide causes defective multimerization and storage of VWF. Blood 115: 4580-4587, 2010. [PubMed: 20335223] [Full Text: https://doi.org/10.1182/blood-2009-09-244327]
Hagiwara, T., Inaba, H., Yoshida, S., Nagaizumi, K., Arai, M., Hanabusa, H., Fukutake, K. A novel mutation gly1672-to-arg in type 2A and a homozygous mutation in type 2B von Willebrand disease. Thromb. Haemost. 76: 253-257, 1996. [PubMed: 8865541]
Hilbert, L., Jorieux, S., Fontenay-Roupie, M., Guicheteau, M., Fressinaud, E., Meyer, D., Mazurier, C., the INSERM Network on Molecular Abnormalities in von Willebrand Disease. Expression of two type 2N von Willebrand disease mutations identified in exon 18 of von Willebrand factor gene. Brit. J. Haemat. 127: 184-189, 2004. [PubMed: 15461624] [Full Text: https://doi.org/10.1111/j.1365-2141.2004.05187.x]
Holmberg, L., Berntorp, E., Donner, M., Nilsson, I. M. von Willebrand's disease characterised by increased ristocetin sensitivity and the presence of all von Willebrand factor multimers. Blood 68: 668-672, 1986. [PubMed: 3488775]
Holmberg, L., Dent, J. A., Schneppenheim, R., Budde, U., Ware, J., Ruggeri, Z. M. von Willebrand factor mutation enhancing interaction with platelets in patients with normal multimeric structure. J. Clin. Invest. 91: 2169-2177, 1993. [PubMed: 8486782] [Full Text: https://doi.org/10.1172/JCI116443]
Holmberg, L., Karpman, D., Isaksson, C., Kristoffersson, A. C., Lethagen, S., Schneppenheim, R. Ins405-asn-pro mutation in the von Willebrand factor propeptide in recessive type 2A (IIC) von Willebrand's disease. Thromb. Haemost. 79: 718-722, 1998. [PubMed: 9569179]
Howard, M. A., Perkin, J., Salem, H. H., Firkin, B. G. The agglutination of human platelets by botrocetin: evidence that botrocetin and ristocetin act at different sites on the factor VIII molecule and platelet membrane. Brit. J. Haemat. 57: 25-35, 1984. [PubMed: 6426499] [Full Text: https://doi.org/10.1111/j.1365-2141.1984.tb02862.x]
Hoyer, L. W. The factor VIII complex: structure and function. Blood 58: 1-13, 1981. [PubMed: 6165414]
Huizinga, E. G., Tsuji, S., Romijn, R. A. P., Schiphorst, M. E., de Groot, P. G., Sixma, J. J., Gros, P. Structures of glycoprotein Ib-alpha and its complex with von Willebrand factor A1 domain. Science 297: 1176-1179, 2002. [PubMed: 12183630] [Full Text: https://doi.org/10.1126/science.107355]
Iannuzzi, M. C., Hidaka, N., Boehnke, M., Bruck, M. E., Hanna, W. T., Collins, F. S., Ginsburg, D. Analysis of the relationship of von Willebrand disease (vWD) and hereditary hemorrhagic telangiectasia and identification of a potential type IIA vWD mutation (ile865-to-thr). Am. J. Hum. Genet. 48: 757-763, 1991. [PubMed: 1673047]
Jackson, S. C., Sinclair, G. D., Cloutier, S., Duan, Z., Rand, M. L., Poon, M.-C. The Montreal platelet syndrome kindred has type 2B von Willebrand disease with the VWF V1316M mutation. Blood 113: 3348-3351, 2009. [PubMed: 19060241] [Full Text: https://doi.org/10.1182/blood-2008-06-165233]
Kokame, K., Matsumoto, M., Fujimura, Y., Miyata, T. VWF73, a region from D1596 to R1668 of von Willebrand factor, provides a minimal substrate for ADAMTS-13. Blood 103: 607-612, 2004. [PubMed: 14512308] [Full Text: https://doi.org/10.1182/blood-2003-08-2861]
Kyrle, P. A., Niessner, H., Dent, J., Panzer, S., Brenner, B., Zimmerman, T. S., Lechner, K. IIB von Willebrand's disease: pathogenetic and therapeutic studies. Brit. J. Haemat. 69: 55-59, 1988. [PubMed: 3132965] [Full Text: https://doi.org/10.1111/j.1365-2141.1988.tb07602.x]
Lavergne, J.-M., De Paillette, L., Bahnak, B. R., Ribba, A.-S., Fressinaud, E., Meyer, D., Pietu, G. Defects in type IIA von Willebrand disease: a cysteine 509 to arginine substitution in the mature von Willebrand factor disrupts a disulphide loop involved in the interaction with platelet glycoprotein Ib-IX. Brit. J. Haemat. 82: 66-72, 1992. [PubMed: 1419804] [Full Text: https://doi.org/10.1111/j.1365-2141.1992.tb04595.x]
Lester, W. A., Guilliatt, A. M., Surdhar, G. K., Enayat, S. M., Wilde, J. T., Willoughby, S., Grundy, P., Cumming, A. M., Collins, P. W., Hill, F. G. H. Inherited and de novo von Willebrand disease 'Vicenza' in UK families with the R1205H mutation: diagnostic pitfalls and new insights. Brit. J. Haemat. 135: 91-96, 2006. [PubMed: 16925796] [Full Text: https://doi.org/10.1111/j.1365-2141.2006.06251.x]
Lynch, D. C., Zimmerman, T. S., Collins, C. J., Morin, M. J., Ling, E. H., Livingston, D. M. Molecular cloning of mRNA for human von Willebrand factor. (Abstract) Clin. Res. 33: 548, 1985.
Lynch, D. C., Zimmerman, T. S., Ruggeri, Z. M. Von Willebrand factor, now cloned. (Annotation). Brit. J. Haemat. 64: 15-20, 1986. [PubMed: 3489483] [Full Text: https://doi.org/10.1111/j.1365-2141.1986.tb07569.x]
Mancuso, D. J., Tuley, E. A., Westfield, L. A., Lester-Mancuso, T. L., Le Beau, M. M., Sorace, J. M., Sadler, J. E. Human von Willebrand factor gene and pseudogene: structural analysis and differentiation by polymerase chain reaction. Biochemistry 30: 253-269, 1991. [PubMed: 1988024] [Full Text: https://doi.org/10.1021/bi00215a036]
Mancuso, D. J., Tuley, E. A., Westfield, L. A., Worrall, N. K., Shelton-Inloes, B. B., Sorace, J. M., Alevy, Y. G., Sadler, J. E. Structure of the gene for human von Willebrand factor. J. Biol. Chem. 264: 19514-19527, 1989. [PubMed: 2584182]
Mannucci, P. M., Lombardi, R., Castaman, G., Dent, J. A., Lattuada, A., Rodeghiero, F., Zimmerman, T. S. Von Willebrand disease 'Vicenza' with larger-than-normal (supranormal) von Willebrand factor multimers. Blood 71: 65-70, 1988. [PubMed: 3257148]
Mazurier, C., Dieval, J., Jorieux, S., Delobel, J., Goudemand, M. A new von Willebrand factor (vWF) defect in a patient with factor VIII (FVIII) deficiency but with normal levels and multimeric patterns of both plasma and platelet vWF: characterization of abnormal vWF/FVIII interaction. Blood 75: 20-26, 1990. [PubMed: 2104761]
Mazurier, C., Gaucher, C., Jorieux, S., Parquet-Gernez, A., Goudemand, M. Evidence for a von Willebrand factor defect in factor VIII binding in three members of a family previously misdiagnosed mild haemophilia A and haemophilia A carriers: consequences for therapy and genetic counselling. Brit. J. Haemat. 76: 372-379, 1990. [PubMed: 2124499] [Full Text: https://doi.org/10.1111/j.1365-2141.1990.tb06371.x]
Mazurier, C., Parquet-Gernez, A., Gaucher, C., Lavergne, J.-M., Goudemand, J. Factor VIII deficiency not induced by FVIII gene mutation in a female first cousin of two brothers with haemophilia A. Brit. J. Haemat. 119: 390-392, 2002. [PubMed: 12406074] [Full Text: https://doi.org/10.1046/j.1365-2141.2002.03819.x]
Mertes, G., Ludwig, M., Schwaab, R., Brackmann, H.-H., Olek, K. Delta C in exon 18 of the von Willebrand gene is uncommon in German vWD type III patients. (Letter) Thromb. Haemost. 70: 1064-1065, 1993. [PubMed: 8165603]
Meyer, D., McKee, P. A., Hoyer, L. W., Zimmerman, T. S., Gralnick, H. R. Molecular biology of factor VIII--von Willebrand factor. Thromb. Haemost. 40: 245-251, 1978. [PubMed: 310584]
Michaux, G., Abbitt, K. B., Collinson, L. M., Haberichter, S. L., Norman, K. E., Cutler, D. F. The physiological function of von Willebrand's factor depends on its tubular storage in endothelial Weibel-Palade bodies. Dev. Cell 10: 223-232, 2006. [PubMed: 16459301] [Full Text: https://doi.org/10.1016/j.devcel.2005.12.012]
Milton, J. G., Frojmovic, M. M., Tang, S. S., White, J. G. Spontaneous platelet aggregation in a hereditary giant platelet syndrome (MPS). Am. J. Path. 114: 336-345, 1984. [PubMed: 6696046]
Murray, E. W., Giles, A. R., Lillicrap, D. Germ-line mosaicism for a valine-to-methionine substitution at residue 553 in the glycoprotein Ib-binding domain of von Willebrand factor, causing type IIB von Willebrand disease. Am. J. Hum. Genet. 50: 199-207, 1992. [PubMed: 1729889]
Nachman, R. L., Jaffe, E. A., Miller, C., Brown, W. T. Structural analysis of factor VIII antigen in von Willebrand disease. Proc. Nat. Acad. Sci. 77: 6832-6836, 1980. [PubMed: 6161373] [Full Text: https://doi.org/10.1073/pnas.77.11.6832]
Ngo, K. Y., Glotz, V. T., Koziol, J. A., Lynch, D. C., Gitschier, J., Ranieri, P., Ciavarella, N., Ruggeri, Z. M., Zimmerman, T. S. Homozygous and heterozygous deletions of the von Willebrand factor gene in patients and carriers of severe von Willebrand disease. Proc. Nat. Acad. Sci. 85: 2753-2757, 1988. [PubMed: 3258663] [Full Text: https://doi.org/10.1073/pnas.85.8.2753]
NIH/CEPH Collaborative Mapping Group. A comprehensive genetic linkage map of the human genome. Science 258: 67-86, 1992. [PubMed: 1439770]
O'Brien, L. A., James, P. D., Othman, M., Berber, E., Cameron, C., Notley, C. R. P., Hegadorn, C. A., Sutherland, J. J., Hough, C., Rivard, G. E., O'Shaunessey, D., Association of Hemophilia Clinic Directors of Canada, Lillicrap, D. Founder von Willebrand factor haplotype associated with type I von Willebrand disease. Blood 102: 549-557, 2003. [PubMed: 12649144] [Full Text: https://doi.org/10.1182/blood-2002-12-3693]
Patracchini, P., Marchetti, G., Aiello, V., Croci, G., Calzolari, E., Bernardi, F. Characterization and mapping of the 5-prime portion of von Willebrand factor pseudogene. Hum. Genet. 90: 297-298, 1992. [PubMed: 1487245] [Full Text: https://doi.org/10.1007/BF00220083]
Peake, I. R., Liddell, M. B., Moodie, P., Standen, G., Mancuso, D. J., Tuley, E. A., Westfield, L. A., Sorace, J. M., Sadler, J. E., Verweij, C. L., Bloom, A. L. Severe type III von Willebrand's disease caused by deletion of exon 42 of the von Willebrand factor gene: family studies that identify carriers of the condition and a compound heterozygous individual. Blood 75: 654-661, 1990. [PubMed: 2297569]
Peerlinck, K., Eikenboom, J. C. J., Ploos Van Amstel, H. K., Sangtawesin, W., Arnout, J., Reitsma, P. H., Vermylen, J., Briet, E. A patient with von Willebrand's disease characterized by a compound heterozygosity for a substitution of arg-854 by gln in the putative factor-VIII-binding domain of von Willebrand factor (vWF) on one allele and very low levels of mRNA from the second vWF allele. Brit. J. Haemat. 80: 358-363, 1992. [PubMed: 1581215] [Full Text: https://doi.org/10.1111/j.1365-2141.1992.tb08145.x]
Rabinowitz, I., Tuley, E. A., Mancuso, D. J., Randi, A. M., Firkin, B. G., Howard, M. A., Sadler, J. E. Von Willebrand disease type B: a missense mutation selectively abolishes ristocetin-induced von Willebrand factor binding to platelet glycoprotein Ib. Proc. Nat. Acad. Sci. 89: 9846-9849, 1992. [PubMed: 1409710] [Full Text: https://doi.org/10.1073/pnas.89.20.9846]
Randi, A. M., Rabinowitz, I., Mancuso, D. J., Mannucci, P. M., Sadler, J. E. Molecular basis of von Willebrand disease type IIB: candidate mutations cluster in one disulfide loop between proposed platelet glycoprotein Ib binding sequences. J. Clin. Invest. 87: 1220-1226, 1991. [PubMed: 2010538] [Full Text: https://doi.org/10.1172/JCI115122]
Randi, A. M., Sacchi, E., Castaman, G. C., Rodeghiero, F., Mannucci, P. M. The genetic defect of type I von Willebrand disease 'Vicenza' is linked to the von Willebrand factor gene. Thromb. Haemost. 69: 173-176, 1993. [PubMed: 8456430]
Rayes, J., Hollestelle, M. J., Legendre, P., Marx, I., de Groot, P. G., Christophe, O. D., Lenting, P. J., Denis, C. V. Mutation and ADAMTS13-dependent modulation of disease severity in a mouse model for von Willebrand disease type 2B. Blood 115: 4870-4877, 2010. [PubMed: 20200350] [Full Text: https://doi.org/10.1182/blood-2009-11-254193]
Riddell, A. F., Gomez, K., Millar, C. M., Mellars, G., Gill, S., Brown, S. A., Sutherland, M., Laffan, M. A., McKinnon, T. A. Characterization of W1745C and S1783A: 2 novel mutations causing defective collagen binding in the A3 domain of von Willebrand factor. Blood 114: 3489-3496, 2009. [PubMed: 19687512] [Full Text: https://doi.org/10.1182/blood-2008-10-184317]
Ruggeri, Z. M., Lombardi, R., Gatti, L., Bader, R., Valsecchi, C., Zimmerman, T. S. Type IIB von Willebrand's disease: differential clearance of endogenous versus transfused large multimer von Willebrand factor. Blood 60: 1453-1456, 1982. [PubMed: 6982737]
Ruggeri, Z. M., Nilsson, I. M., Lombardi, R., Holmberg, L., Zimmerman, T. S. Aberrant multimeric structure of von Willebrand factor in a new variant of von Willebrand's disease (type IIC). J. Clin. Invest. 70: 1124-1127, 1982. [PubMed: 6982283] [Full Text: https://doi.org/10.1172/jci110700]
Ruggeri, Z. M., Pareti, F. I., Mannucci, P. M., Ciavarella, N., Zimmerman, T. S. Heightened interaction between platelets and factor VIII von Willebrand factor in a new subtype of von Willebrand's disease. New Eng. J. Med. 302: 1047-1051, 1980. [PubMed: 6767976] [Full Text: https://doi.org/10.1056/NEJM198005083021902]
Ruggeri, Z. M., Zimmerman, T. S. Variant von Willebrand's disease: characterization of two subtypes by analysis of multimeric composition of factor VIII-von Willebrand factor in plasma and platelets. J. Clin. Invest. 65: 1318-1325, 1980. [PubMed: 6773982] [Full Text: https://doi.org/10.1172/JCI109795]
Ruggeri, Z. M. Von Willebrand factor. J. Clin. Invest. 99: 559-564, 1997. Note: Erratum: J. Clin. Invest. 100: 237 only, 1997. [PubMed: 9045854] [Full Text: https://doi.org/10.1172/JCI119195]
Saba, H. I., Saba, S. R., Dent, J., Ruggeri, Z. M., Zimmerman, T. S. Type IIB Tampa: a variant of von Willebrand disease with chronic thrombocytopenia, circulating platelet aggregates, and spontaneous platelet aggregation. Blood 66: 282-286, 1985. [PubMed: 3926021]
Sadler, J. E., Budde, U., Eikenboom, J. C. J., Favaloro, E. J., Hill, F. G. H., Holmberg, L., Ingerslev, J., Lee, C. A., Lillicrap, D., Mannucci, P. M., Mazurier, C., Meyer, D., and 9 others. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J. Thromb. Haemost. 4: 2103-2114, 2006. [PubMed: 16889557] [Full Text: https://doi.org/10.1111/j.1538-7836.2006.02146.x]
Sadler, J. E., Ginsburg, D. A database of polymorphisms in the von Willebrand factor gene and pseudogene. Thromb. Haemost. 69: 185-191, 1993. [PubMed: 8456432]
Sadler, J. E., Shelton-Inloes, B. B., Sorace, J. M., Harlan, J. M., Titani, K., Davie, E. W. Cloning and characterization of two cDNAs coding for human von Willebrand factor. Proc. Nat. Acad. Sci. 82: 6394-6398, 1985. [PubMed: 2864688] [Full Text: https://doi.org/10.1073/pnas.82.19.6394]
Schneppenheim, R., Brassard, J., Krey, S., Budde, U., Kunicki, T. J., Holmberg, L., Ware, J., Ruggeri, Z. M. Defective dimerization of von Willebrand factor subunits due to a cys-to-arg mutation in type IID von Willebrand disease. Proc. Nat. Acad. Sci. 93: 3581-3586, 1996. [PubMed: 8622978] [Full Text: https://doi.org/10.1073/pnas.93.8.3581]
Schneppenheim, R., Federici, A. B., Budde, U., Castaman, G., Drewke, E., Krey, S., Mannucci, P. M., Riesen, G., Rodeghiero, F., Zieger, B., Zimmermann, R. Von Willebrand disease type 2M 'Vicenza' in Italian and German patients: identification of the first candidate mutation (G3864A; R1205H) in 8 families. Thromb. Haemost. 83: 136-140, 2000. [PubMed: 10669167]
Schneppenheim, R., Michiels, J. J., Obser, T., Oyen, F., Pieconka, A., Schneppenheim, S., Will, K., Zieger, B., Budde, U. A cluster of mutations in the D3 domain of von Willebrand factor correlates with a distinct subgroup of von Willebrand disease: type 2A/IIE. Blood 115: 4894-4901, 2010. [PubMed: 20351307] [Full Text: https://doi.org/10.1182/blood-2009-07-226324]
Schneppenheim, R., Thomas, K. B., Krey, S., Budde, U., Jessat, U., Sutor, A. H., Zieger, B. Identification of a candidate missense mutation in a family with von Willebrand disease type IIC. Hum. Genet. 95: 681-686, 1995. [PubMed: 7789955] [Full Text: https://doi.org/10.1007/BF00209487]
Shelton-Inloes, B. B., Chehab, F. F., Mannucci, P. M., Federici, A. B., Sadler, J. E. Gene deletions correlate with the development of alloantibodies in von Willebrand disease. J. Clin. Invest. 79: 1459-1465, 1987. [PubMed: 3033024] [Full Text: https://doi.org/10.1172/JCI112974]
Sporn, L. A., Marder, V. J., Wagner, D. D. Von Willebrand factor released from Weibel-Palade bodies binds more avidly to extracellular matrix than that secreted constitutively. Blood 69: 1531-1534, 1987. [PubMed: 3105624]
Stepanian, A., Ribba, A.-S., Lavergne, J.-M., Fressinaud, E., Juhan-Vague, I., Mazurier, C., Girma, J.-P., Meyer, D. A new mutation, S1285F, within the A1 loop of von Willebrand factor induces a conformational change in A1 loop with abnormal binding to platelet GPIb and botrocetin causing type 2M von Willebrand disease. Brit. J. Haemat. 120: 643-651, 2003. [PubMed: 12588351] [Full Text: https://doi.org/10.1046/j.1365-2141.2003.04168.x]
Sutherland, M. S., Cumming, A. M., Bowman, M., Bolton-Maggs, P. H. B., Bowen, D. J., Collins, P. W., Hay, C. R. M., Will, A. M., Keeney, S. A novel deletion mutation is recurrent in von Willebrand disease types 1 and 3. Blood 114: 1091-1098, 2009. [PubMed: 19372260] [Full Text: https://doi.org/10.1182/blood-2008-08-173278]
Titani, K., Kumar, S., Takio, K., Ericsson, L. H., Wade, R. D., Ashida, K., Walsh, K. A., Chopek, M. W., Sadler, J. E., Fujikawa, K. Amino acid sequence of human von Willebrand factor. Biochemistry 25: 3171-3184, 1986. [PubMed: 3524673] [Full Text: https://doi.org/10.1021/bi00359a015]
Tjernberg, P., Castaman, G., Vos, H. L., Bertina, R. M., Eikenboom, J. C. Homozygous C2362F von Willebrand factor induces intracellular retention of mutant von Willebrand factor resulting in autosomal recessive severe von Willebrand disease. Brit. J. Haemat. 133: 409-418, 2006. [PubMed: 16643449] [Full Text: https://doi.org/10.1111/j.1365-2141.2006.06055.x]
Tuley, E. A., Gaucher, C., Jorieux, S., Worrall, N. K., Sadler, J. E., Mazurier, C. Expression of von Willebrand factor 'Normandy': an autosomal mutation that mimics hemophilia A. Proc. Nat. Acad. Sci. 88: 6377-6381, 1991. [PubMed: 1906179] [Full Text: https://doi.org/10.1073/pnas.88.14.6377]
Verweij, C. L., de Vries, C. J. M., Distel, B., van Zonneveld, A.-J., Geurts van Kessel, A., van Mourik, J. A., Pannekoek, H. Construction of cDNA coding for human von Willebrand factor using antibody probes for colony-screening and mapping of the chromosomal gene. Nucleic Acids Res. 13: 4699-4717, 1985. [PubMed: 3875078] [Full Text: https://doi.org/10.1093/nar/13.13.4699]
Verweij, C. L., Hofker, M., Quadt, R., Briet, E., Pannekoek, H. RFLP for a human von Willebrand factor (vWF) cDNA clone, pvWF1100. Nucleic Acids Res. 13: 8289 only, 1985. Note: Erratum: Nucleic Acids Res. 14: 1930 only, 1986. [PubMed: 3877913] [Full Text: https://doi.org/10.1093/nar/13.22.8289]
von Willebrand, E. A. Hereditar pseudohemofili. Finska Lakar. Hand. 68: 87-112, 1926.
Wagner, D. D., Saffaripour, S., Bonfanti, R., Sadler, J. E., Cramer, E. M., Chapman, B., Mayadas, T. N. Induction of specific storage organelles by von Willebrand factor propolypeptide. Cell 64: 403-413, 1991. [PubMed: 1988154] [Full Text: https://doi.org/10.1016/0092-8674(91)90648-i]
Ware, J., Dent, J. A., Azuma, H., Sugimoto, M., Kyrle, P. A., Yoshioka, A., Ruggeri, Z. M. Identification of a point mutation in type IIB von Willebrand disease illustrating the regulation of von Willebrand factor affinity for the platelet membrane glycoprotein Ib-IX receptor. Proc. Nat. Acad. Sci. 88: 2946-2950, 1991. [PubMed: 2011604] [Full Text: https://doi.org/10.1073/pnas.88.7.2946]
Weiss, J. G., Sussman, I. I. Increased ristocetin-induced platelet aggregation (RIPA) and plasma von Willebrand factor (VWF) containing all VWF multimers (type I--New York). (Abstract) Blood 66 (suppl. 1): 329, 1985.
Wise, R. J., Ewenstein, B. M., Gorlin, J., Narins, S. C., Jesson, M., Handin, R. I. Autosomal recessive transmission of hemophilia A due to a von Willebrand factor mutation. Hum. Genet. 91: 367-372, 1993. [PubMed: 8500791] [Full Text: https://doi.org/10.1007/BF00217358]
Wu, J.-J., Fujikawa, K., McMullen, B. A., Chung, D. W. Characterization of a core binding site for ADAMTS-13 in the A2 domain of von Willebrand factor. Proc. Nat. Acad. Sci. 103: 18470-18474, 2006. [PubMed: 17121983] [Full Text: https://doi.org/10.1073/pnas.0609190103]
Wylie, B., Gibson, J., Uhr, E., Kronenberg, H. Von Willebrand's disease characterized by increased ristocetin sensitivity and the presence of all von Willebrand factor multimers in plasma: a new subtype. Pathology 20: 62-63, 1988. [PubMed: 3259690] [Full Text: https://doi.org/10.3109/00313028809085199]
Zhang, Z. P., Blomback, M., Nyman, D., Anvret, M. Mutations of von Willebrand factor gene in families with von Willebrand disease in the Aland Islands. Proc. Nat. Acad. Sci. 90: 7937-7940, 1993. [PubMed: 8367445] [Full Text: https://doi.org/10.1073/pnas.90.17.7937]
Zhang, Z. P., Falk, G., Blomback, M., Egberg, N., Anvret, M. A single cytosine deletion in exon 18 of the von Willebrand factor gene is the most common mutation in Swedish vWD type III patients. Hum. Molec. Genet. 1: 767-768, 1992. [PubMed: 1302613] [Full Text: https://doi.org/10.1093/hmg/1.9.767]
Zhang, Z. P., Falk, G., Blomback, M., Egberg, N., Anvret, M. Identification of a new nonsense mutation in the von Willebrand factor gene in patients with von Willebrand disease type III. Hum. Molec. Genet. 1: 61-62, 1992. [PubMed: 1301136] [Full Text: https://doi.org/10.1093/hmg/1.1.61]
Zhang, Z. P., Lindstedt, M., Falk, G., Blomback, M., Egberg, N., Anvret, M. Nonsense mutations of the von Willebrand factor gene in patients with von Willebrand disease type III and type I. Am. J. Hum. Genet. 51: 850-858, 1992. [PubMed: 1415226]
Zhou, M., Dong, X., Baldauf, C., Chen, H., Zhou, Y., Springer, T. A., Luo, X., Zhong, C., Grater, F., Ding, J. A novel calcium-binding site of von Willebrand factor A2 domain regulates its cleavage by ADAMTS13. Blood 117: 4623-4631, 2011. [PubMed: 21385852] [Full Text: https://doi.org/10.1182/blood-2010-11-321596]
Zieger, B., Budde, U., Jessat, U., Zimmermann, R., Simon, M., Katzel, R., Sutor, A. H. New families with von Willebrand disease type 2M (Vicenza). Thromb. Res. 87: 57-64, 1997. [PubMed: 9253800] [Full Text: https://doi.org/10.1016/s0049-3848(97)00104-7]