Identification of a homozygous Cys410Ser mutation in the von Willebrand factor D2 domain causing type 2A(<scp>IIC</scp>) von Willebrand disease phenotype in an Iranian patient

Enayat, M. S.; Rassoulzadegan, M.; Jazebi, Mohammad; Ala, F.; Budde, Ulrich; Schneppenheim, Sonja; Obser, Tobias; Schneppenheim, Reinhard

doi:10.1111/hae.12161

Cited by 4 publications

(3 citation statements)

References 8 publications

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“…Defects in N-terminal dimerization can be caused by two different mechanisms. First, homozygous mutations in the propeptide (D1 and D2 domains) of VWF, or patients being compound heterozygous for a propeptide mutation and a null allele, are associated with severely affected multimerization and intracellular retention and are described as both subtype 2A (IIC) and type 3 VWD [63,[68][69][70][71][72]. Co-expression of normal and mutant VWF constructs in heterologous cell systems show a normal multimers profile and heterozygous carriers of propeptide mutations are unaffected or diagnosed with VWD type 1 [72].…”

Section: Intracellular Multimerization Defectsmentioning

confidence: 99%

Von Willebrand disease mutation spectrum and associated mutation mechanisms

Jong

Eikenboom

2017

Thrombosis Research

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Section: Intracellular Multimerization Defectsmentioning

confidence: 99%

Von Willebrand disease mutation spectrum and associated mutation mechanisms

Jong

Eikenboom

2017

Thrombosis Research

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“…Because exons 9 and 10 contain several cysteine codons, the duplicated amino acids may also directly interfere with multimerization. Three cysteine mutations in the VWFD2 domain causing VWD2AIIC and several examples of cysteine mutations in the VWFD3 domain causing multimerization deficits support this idea.…”

Section: Discussionmentioning

confidence: 83%

“…This last post‐translational step is mediated by the VWF‐propeptide (VWFpp) . Hence, some mutations located in VWFpp also correlate with a profound multimerization deficit . The corresponding phenotype was originally described as VWD subtype IIC (VWD2AIIC), characterized by low VWF antigen (VWF:Ag), decreased platelet‐dependent function (low ristocetin‐cofactor [VWF:RCo]) and lack of VWF HMWM, which in medium resolution multimer analysis show a virtually complete absence of proteolytic sub‐bands of individual VWF oligomers .…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of the elusive mutation causing the historical von Willebrand Disease type IIC Miami

Obser

Ledford‐Kraemer²,

Oyen

et al. 2016

Journal of Thrombosis and Haemostasis

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Summary Background A variant of von Willebrand disease (VWD) type 2A, phenotype IIC (VWD2AIIC) is characterized by recessive inheritance, low von Willebrand factor antigen (VWF:Ag), lack of VWF high molecular weight multimers, absence of VWF proteolytic fragments, and mutations in the VWF propeptide. A family with dominantly inherited VWD2AIIC but markedly elevated VWF:Ag of >2 U/L was described as VWD type IIC Miami (VWD2AIIC-Miami) in 1993, however the molecular defect remained elusive. Objectives To identify the molecular mechanism underlying the phenotype of the original VWD2AIIC-Miami. Patients and Methods We studied the original family with VWD2AIIC-Miami phenotypically and by genotyping. The identified mutation was recombinantly expressed and characterized by standard techniques, confocal imaging, and in a mouse model, respectively. Results By Multiplex ligation-dependent probe amplification we identified an in-frame duplication of VWF exons 9-10 (c.998_1156dup; p.Glu333_385dup) in all patients. Recombinant mutant (rm)VWF only presented as a dimer. Co-expressed with wild type VWF, the multimer pattern was indistinguishable from patients’ plasma VWF. Immunofluorescence studies indicated retention of rmVWF in unusually large intracellular granules in the Endoplasmic Reticulum. ADAMTS13 proteolysis of rmVWF under denaturing conditions was normal, however an aberrant proteolytic fragment was apparent. A decreased ratio of VWF propeptide to VWF:Ag and a DDAVP test in one patient indicated delayed VWF clearance which was supported by clearance data after infusion of rmVWF into VWF−/− mice. Conclusion The unique phenotype of VWD2 type IIC-Miami results from dominant impairment of multimer assembly, an aberrant structure of mutant mature VWF, and reduced clearance in vivo.

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