Faculty Collaboration Database

Identification and characterization of the elusive mutation causing the historical von Willebrand Disease type IIC Miami. J Thromb Haemost 2016 Sep;14(9):1725-35

Date

06/28/2016

Pubmed ID

27344059

Pubmed Central ID

PMC5035592

DOI

10.1111/jth.13398

Scopus ID

2-s2.0-84988462405 (requires institutional sign-in at Scopus site)   9 Citations

Abstract

UNLABELLED: Essentials Von Willebrand disease IIC Miami features high von Willebrand factor (VWF) with reduced function. We aimed to identify and characterize the elusive underlying mutation in the original family. An inframe duplication of VWF exons 9-10 was identified and characterized. The mutation causes a defect in VWF multimerization and decreased VWF clearance from the circulation.

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(-1) 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. ADAMTS-13 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 1-desamino-8-d-arginine vasopressin (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.

Author List

Obser T, Ledford-Kraemer M, Oyen F, Brehm MA, Denis CV, Marschalek R, Montgomery RR, Sadler JE, Schneppenheim S, Budde U, Schneppenheim R

Author

Robert R. Montgomery MD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Animals
Deamino Arginine Vasopressin
Endoplasmic Reticulum
Female
Genes, Dominant
Genes, Recessive
Genotype
Humans
Male
Mice
Mice, Inbred C57BL
Middle Aged
Mutation
Phenotype
Recombinant Proteins
von Willebrand Disease, Type 2
von Willebrand Factor