Molecular Background of 'Smeary' von Willebrand Factor Multimers
| Autor: | Florian Oyen, Ulrich Budde, Heike Eckert, Reinhard Schneppenheim, Antje Pieconka, Sonja Schneppenheim, Tobias Obser, Kerstin Will, Olivier Marggraf |
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| Rok vydání: | 2007 |
| Předmět: |
Genetics
congenital hereditary and neonatal diseases and abnormalities biology Von Willebrand factor type A domain Chemistry Immunology Mutant Wild type Cell Biology Hematology medicine.disease Biochemistry Phenotype Molecular biology law.invention Genotype-phenotype distinction Von Willebrand factor law hemic and lymphatic diseases Von Willebrand disease medicine biology.protein Recombinant DNA circulatory and respiratory physiology |
| Zdroj: | Blood. 110:2711-2711 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Background: Multimer analysis of von Willebrand factor (VWF) is a most important technique to classify patients with von Willebrand disease (VWD) type 2. Besides “classical” multimer patterns a “smeary” appearance of individual VWF oligomers is increasingly observed and has previously been regarded as a pre-analytical artifact. Objective: To phenotypically and genotypically assess the molecular background of “smeary” VWF multimers. Patients and methods: Samples of 8 VWD patients were analyzed in our reference lab (UB) for further classification and molecular testing. Multimer profiles were assessed by intermediate resolution gels. VWF:CB and VWF:GpIb binding were used as functional assays. VWF gene mutation analysis was performed in all index cases (IC). The causal relationship between genotype and phenotype was studied by analyzing recombinant mutants in comparison to wildtype VWF. Results: In all IC the phenotype correlated with particular mutations in the VWF D3 domain (G1172D), the A1 domain (R1315C, R1374S, R1374C, R1399C), the D4 domain (C2257R), the C1 domain (R2464C) and in the region close to the CK domain (C2671Y), respectively. The multimer patterns of recombinant mutant VWF was of a “smeary” appearance and closely resembled those of mutant plasma VWF. Mutations in the A1 domain additionally correlated with severe GpIb binding deficiency. Conclusions: Our data suggest a molecular cause of the “smeary” multimer structure rather than pre-analytical artifacts. Most of the mutations identified involved cysteine residues suggesting an influence on the VWF secondary structure which is determined by intra- and intermolecular disulfide bonds. This could explain the peculiar multimer appearance. The functional deficits, however, seem to depend on the location of the mutations with a significant impact on GpIb binding of mutants in the A1 domain. |
| Databáze: | OpenAIRE |
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