Identification and characterization of the elusive mutation causing the historical von Willebrand Disease type IIC Miami
| Autor: | J E Sadler, Tobias Obser, Sonja Schneppenheim, Reinhard Schneppenheim, Florian Oyen, U. Budde, M. Ledford-Kraemer, Rolf Marschalek, Cécile V. Denis, Maria A. Brehm, Robert R. Montgomery |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Adult Male congenital hereditary and neonatal diseases and abnormalities Genotype Mutant Genes Recessive von Willebrand Disease Type 2 030204 cardiovascular system & hematology medicine.disease_cause Endoplasmic Reticulum Article 03 medical and health sciences Exon Mice 0302 clinical medicine Von Willebrand factor hemic and lymphatic diseases von Willebrand Factor medicine Von Willebrand disease Animals Humans Deamino Arginine Vasopressin Protein precursor Aged Genes Dominant Mutation biology Chemistry Hematology Middle Aged medicine.disease Phenotype Molecular biology ADAMTS13 Recombinant Proteins Mice Inbred C57BL 030104 developmental biology cardiovascular system biology.protein Female circulatory and respiratory physiology |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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