Molekulare Genetik des von-Willebrand-Syndroms

Zusammenfassung

Die multifunktionellen Eigenschaften des von Willebrand-Faktors (VWF) und seine komplexe Biosynthese und Struktur sind für die unterschiedlichen molekularen Mechanismen verantwortlich, welche die bekannte ausgeprägte klinische Heterogenität des von Willebrand-Syndroms (VWS) erklären. Die Identifizierung spezifischer Mutationen, die entweder mit dem kompletten oder partiellen Fehlen des VWF, Störungen der posttranslationalen Modifikation, wie Dimerisierung und Multimerisierung, Beeinträchtigung des intrazellulären Transports oder funktionellen Defekten einhergehen, haben die Möglichkeit für Struktur/Funktions-Studien des VWF und zu Genotyp/Phänotyp-Analysen des VWS geschaffen. Durch die heute verfügbare moderne Technik der Genanalyse können selbst bei dem sehr großen und komplexen Gen des VWF mit seinen 52 Exons die kausalen Mutationen in einer überschaubaren Zeit identifiziert werden. Die Mutationsanalyse kann somit bei der korrekten Diagnosestellung und der Klassifikation von Patienten hilfreich sein, was für viele Patienten für die Wahl der adäquaten Therapie von Bedeutung ist. Auch die Identifizierung von nicht betroffenen Mutationsträgern innerhalb einer Familie mit VWS ist hierdurch möglich. Darüberhinaus können die Mutationsanalyse und die aus ihr gewonnenen Erkenntnisse dazu beitragen, die molekularen Mechanismen des VWF nicht nur bei Blutungen sondern auch bei arteriellen thromboembolischen Erkrankungen zu verstehen.

Summary

Due to the multifunctional character of von Willebrand factor (VWF), its complex biosynthesis and structure, many different disease causing molecular mechanisms exist which explain the well known marked heterogeneity of clinical symptoms in von Willebrand disease (VWD). Identification of specific mutations that can either cause complete or partial absence of VWF, interfere with post-translation processing of VWF like dimerisation and multimerisation, impair intracellular transport or disturb particular functions of VWF, offered the opportunity for structure/function studies of VWF and genotype/phenotype analysis of VWD. Today the molecular tools for such studies are readily available, enabling us to identify the molecular defects in a reasonable time even in the case of the large and complex VWF gene with its 52 exons. Mutation analysis can help to find the correct diagnosis and to classify patients with VWD which may be crucial to choose the adequate therapy. It can also identify unaffected carriers of the disease gene among family members of patients with VWD. Furthermore, mutation analysis and the conclusions drawn from such data can further help to understand the molecular mechanisms of VWF not only in bleeding but also in arterial thrombotic disease.

Schlüsselwörter

VWF - VWS - Genetik

Keywords

VWF - VWD - genetics

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