Identification of a homozygous missense mutation (p.Cys379Gly) in the D1 domain of von Willebrand factor propeptide in a family with type 2A (IIC) von Willebrand disease

Haemophilia ◽  
2018 ◽  
Vol 24 (6) ◽  
pp. e422-e425
Author(s):  
Toshio Shigekiyo ◽  
Kengo Udaka ◽  
Etsuko Sekimoto ◽  
Hironobu Shibata ◽  
Shuji Ozaki ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Homozygous Missense Mutation ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Von Willebrand Factor Propeptide

scholarly journals von Willebrand factor propeptide: biology and clinical utility

Blood ◽  
2015 ◽  
Vol 126 (15) ◽  
pp. 1753-1761 ◽  
Author(s):  
Sandra L. Haberichter
Keyword(s):  
Von Willebrand Factor ◽  
Clinical Utility ◽  
Coagulation Factor ◽  
Von Willebrand Disease ◽  
True Type ◽  
And Function ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Von Willebrand Factor Propeptide

Abstract von Willebrand factor (VWF) is a large multimeric glycoprotein that mediates the attachment of platelets to damaged endothelium and also serves as the carrier protein for coagulation factor VIII (FVIII), protecting it from proteolytic degradation. Quantitative or qualitative defects in VWF result in von Willebrand disease (VWD), a common inherited bleeding disorder. VWF is synthesized with a very large propeptide (VWFpp) that is critical for intracellular processing of VWF. VWFpp actively participates in the process of VWF multimerization and is essential for trafficking of VWF to the regulated storage pathway. Mutations identified within VWFpp in VWD patients are associated with altered VWF structure and function. The assay of plasma VWFpp has clinical utility in assessing acute and chronic vascular perturbation associated with diseases such as thrombotic thrombocytopenic purpura, sepsis, and diabetes among others. VWFpp assay also has clear utility in the diagnosis of VWD subtypes, particularly in discriminating true type 3 subjects from type 1C (reduced plasma survival of VWF), which is clinically important and has implications for therapeutic treatment.

Identification of a missense mutation (p.Leu1733Pro) in the A3 domain of von Willebrand factor in a family with type 2M von Willebrand disease

2019 ◽  
Vol 111 (3) ◽  
pp. 467-470
Author(s):  
Toshio Shigekiyo ◽  
Hikaru Yagi ◽  
Etsuko Sekimoto ◽  
Hironobu Shibata ◽  
Shuji Ozaki ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Von Willebrand ◽  
Willebrand Factor

Identification of a New Type 2M von Willebrand Disease Mutation also at Position 1324 of von Willebrand Factor

2002 ◽  
Vol 87 (04) ◽  
pp. 635-640 ◽  
Author(s):  
E. Fressinaud ◽  
A. S. Ribba ◽  
D. Meyer ◽  
C. Mazurier ◽  
L. Hilbert ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Von Willebrand Factor ◽  
Stop Codon ◽  
Von Willebrand Disease ◽  
Platelet Glycoprotein ◽  
Patient Reported ◽  
French Family ◽  
New Type ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryType 2M von Willebrand disease (VWD) refers to variants with decreased platelet-dependent function that is not associated with the loss of high molecular weight (HMW) von Willebrand factor (VWF) multimers. This category includes the so-called “phenotype B” responsible for inexistent ristocetin-induced but normal botrocetin-induced binding of VWF to platelet glycoprotein Ib. The missense mutation G1324S was identified in the first patient reported to display “phenotype B”.We report here on the identification in four members of a French family of a missense mutation also affecting this glycine residue but changing it into an alanine residue. These individuals are heterozygous for this mutation and two of them display an additional quantitative VWF deficiency resulting from a stop codon at position 2470. After transient transfection in Cos-7 cells, the mutated recombinant protein harbouring the G1324A substitution was shown to exhibit normal multimers and inexistent ristocetin-induced but normal botrocetininduced binding to GPIb, confirming the classification of this new mutation as a type 2M VWD mutation.

scholarly journals von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease

Blood ◽  
2015 ◽  
Vol 125 (19) ◽  
pp. 3006-3013 ◽  
Author(s):  
Yvonne V. Sanders ◽  
Dafna Groeneveld ◽  
Karina Meijer ◽  
Karin Fijnvandraat ◽  
Marjon H. Cnossen ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Key Points ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Severe Type ◽  
Von Willebrand Factor Propeptide

Key Points VWFpp discriminates between type 3 VWD patients and severe type 1 VWD patients with very low VWF levels. The pathophysiological mechanisms of all types of VWD can be defined by the combined ratios of VWFpp/VWF:Ag and FVIII:C/VWF:Ag.

scholarly journals Type 2M von Willebrand Disease: F606I and I662F Mutations in the Glycoprotein Ib Binding Domain Selectively Impair Ristocetin- but not Botrocetin-Mediated Binding of von Willebrand Factor to Platelets

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1572-1581 ◽  
Author(s):  
Cheryl A. Hillery ◽  
David J. Mancuso ◽  
J. Evan Sadler ◽  
Jay W. Ponder ◽  
Mary A. Jozwiak ◽  
...  
Keyword(s):  
Amino Acid ◽  
Missense Mutation ◽  
Von Willebrand Factor ◽  
Amino Acid Substitution ◽  
Von Willebrand Disease ◽  
Glycoprotein Ib ◽  
Collagen Binding ◽  
Platelet Binding ◽  
Von Willebrand ◽  
Willebrand Factor

Abstractvon Willebrand disease (vWD) is a common, autosomally inherited, bleeding disorder caused by quantitative and/or qualitative deficiency of von Willebrand factor (vWF). We describe two families with a variant form of vWD where affected members of both families have borderline or low vWF antigen levels, normal vWF multimer patterns, disproportionately low ristocetin cofactor activity, and significant bleeding symptoms. Whereas ristocetin-induced binding of plasma vWF from affected members of both families to fixed platelets was reduced, botrocetin-induced platelet binding was normal. The sequencing of genomic DNA identified unique missense mutations in each family in the vWF exon 28. In Family A, a missense mutation at nucleotide 4105T → A resulted in a Phe606Ile amino acid substitution (F606I) and in Family B, a missense mutation at nucleotide 4273A → T resulted in an Ile662Phe amino acid substitution (I662F). Both mutations are within the large disulfide loop between Cys509 and Cys695 in the A1 domain that mediates vWF interaction with platelet glycoprotein Ib. Expression of recombinant vWF containing either F606I or I662F mutations resulted in mutant recombinant vWF with decreased ristocetin-induced platelet binding, but normal multimer structure, botrocetin-induced platelet binding, collagen binding, and binding to the conformation-sensitive monoclonal antibody, AvW-3. Both mutations are phenotypically distinct from the previously reported variant type 2MMilwaukee-1 because of the presence of normal botrocetin-induced platelet binding, collagen binding, and AvW-3 binding, as well as the greater frequency and intensity of clinical bleeding. When the reported type 2M mutations are mapped on the predicted three-dimensional structure of the A1 loop of vWF, the mutations cluster in one region that is distinct from the region in which the type 2B mutations cluster.

scholarly journals Type 2M von Willebrand Disease: F606I and I662F Mutations in the Glycoprotein Ib Binding Domain Selectively Impair Ristocetin- but not Botrocetin-Mediated Binding of von Willebrand Factor to Platelets

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1572-1581 ◽  
Author(s):  
Cheryl A. Hillery ◽  
David J. Mancuso ◽  
J. Evan Sadler ◽  
Jay W. Ponder ◽  
Mary A. Jozwiak ◽  
...  
Keyword(s):  
Amino Acid ◽  
Missense Mutation ◽  
Von Willebrand Factor ◽  
Amino Acid Substitution ◽  
Von Willebrand Disease ◽  
Glycoprotein Ib ◽  
Collagen Binding ◽  
Platelet Binding ◽  
Von Willebrand ◽  
Willebrand Factor

von Willebrand disease (vWD) is a common, autosomally inherited, bleeding disorder caused by quantitative and/or qualitative deficiency of von Willebrand factor (vWF). We describe two families with a variant form of vWD where affected members of both families have borderline or low vWF antigen levels, normal vWF multimer patterns, disproportionately low ristocetin cofactor activity, and significant bleeding symptoms. Whereas ristocetin-induced binding of plasma vWF from affected members of both families to fixed platelets was reduced, botrocetin-induced platelet binding was normal. The sequencing of genomic DNA identified unique missense mutations in each family in the vWF exon 28. In Family A, a missense mutation at nucleotide 4105T → A resulted in a Phe606Ile amino acid substitution (F606I) and in Family B, a missense mutation at nucleotide 4273A → T resulted in an Ile662Phe amino acid substitution (I662F). Both mutations are within the large disulfide loop between Cys509 and Cys695 in the A1 domain that mediates vWF interaction with platelet glycoprotein Ib. Expression of recombinant vWF containing either F606I or I662F mutations resulted in mutant recombinant vWF with decreased ristocetin-induced platelet binding, but normal multimer structure, botrocetin-induced platelet binding, collagen binding, and binding to the conformation-sensitive monoclonal antibody, AvW-3. Both mutations are phenotypically distinct from the previously reported variant type 2MMilwaukee-1 because of the presence of normal botrocetin-induced platelet binding, collagen binding, and AvW-3 binding, as well as the greater frequency and intensity of clinical bleeding. When the reported type 2M mutations are mapped on the predicted three-dimensional structure of the A1 loop of vWF, the mutations cluster in one region that is distinct from the region in which the type 2B mutations cluster.

Identifying Carriers of Type 2N von Willebrand Disease

2007 ◽  
Vol 13 (2) ◽  
pp. 194-200 ◽  
Author(s):  
A. Casonato ◽  
E. Pontara ◽  
F. Sartorello ◽  
M.G. Cattini ◽  
P. Perutelli ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Von Willebrand Factor ◽  
Hemophilia A ◽  
Von Willebrand Disease ◽  
Retrospective Evaluation ◽  
Laboratory Parameters ◽  
Diagnostic Capacity ◽  
Von Willebrand ◽  
Willebrand Factor

The defective FVIII carrier function of von Willebrand factor (VWF) identifies type 2N von Willebrand disease (VWD), a variant with a pattern resembling hemophilia A. Type 2N characterization is based on the evaluation of the capacity of VWF to bind exogenous FVIII (VWF:FVIIIB). Here we report on a retrospective evaluation of hemostatic laboratory parameters most useful in detecting type 2N carriers. The diagnostic capacity of aPTT, FVIII, VWF:Ag, FVIII/VWF:Ag ratio, VWF:FVIIIB and VWF:FVIIIB/VWF:Ag ratio was evaluated in 21 type 2N VWD carriers. Twenty subjects were heterozygous for the R854Q mutation, one was heterozygous for the R760C missense mutation, which interferes with cleavage of the VWF propeptide. We found that prolongation of aPTT and decrease in FVIII and FVIII/VWF:Ag ratio were not frequent findings in type 2N carriers. The same was true for VWF:FVIIIB which was not always abnormal. On the contrary, VWF:FVIIIB/VWF:Ag ratio was always defective and its values were not related with FVIII and FVIII/VWF:Ag ratio or influenced by plasma VWF concentration. Given these results, we attribute the greatest significance to VWF:FVIIIB/VWF:Ag ratio in the diagnosis of type 2N defects, and only search for type 2N mutations, to validate the diagnosis, if the ratio proves abnormal.

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