Phenotypic approaches to gene mapping in platelet function disorders

Summary

Platelet number or function disorders cause a range of bleeding symptoms from mild to severe. Patients with platelet dysfunction but normal platelet number are the most prevalent and typically have mild bleeding symptoms. The study of this group of patients is particularly difficult because of the lack of a gold-standard test of platelet function and the variable penetrance of the bleeding phenotype among affected individuals.

The purpose of this short review is to discuss the way in which this group of patients can be investigated through platelet phenotyping in combination with targeted gene sequencing. This approach has been used recently to identify patients with mutations in key platelet activation receptors, namely those for ADP, collagen and thromboxane A₂ (TxA₂). One interesting finding from this work is that for some patients, mild bleeding is associated with heterozygous mutations in platelet proteins that are co-inherited with other genetic disorders of haemostasis such as type 1 von Willebrand‘s disease. Thus, the phenotype of mild bleeding may be multifactorial in some patients and may be considered to be a complex trait.

Zusammenfassung

Störungen der Thrombozytenzahl oder -funktion führen zu einer Reihe von leichten bis schweren Blutungssymptomen. Patienten mit Thrombozytendysfunktion, aber normaler Thrombozytenzahl zeigen die höchste Prävalenz, haben aber üblicherweise nur leichte Blutungen. Die Untersuchung dieser Patientengruppe gestaltet sich besonders schwierig, da kein Goldstandard-Test für die Thrombozytenfunktion existiert und die Penetranz des Blutungsphänotyps bei den Betroffenen individuell variiert.

Mit dieser kurzen Übersicht soll dargestellt werden, wie diese Patientengruppe mittels Thrombozytenphänotypisierung in Kombi-nation mit der Sequenzierung von Zielgenen untersucht werden kann. Dieser Ansatz wurde kürzlich zur Identifizierung von Patienten genutzt, die Mutationen in Schlüsselrezeptoren der Thrombozytenaktivierung aufweisen, nämlich den Rezeptoren für ADP, Kollagen und Thromboxan A₂ (TxA₂). Ein interessantes Ergebnis ist, dass bei einigen Patienten leichte Blutungen mit heterozygoten Mutationen in Thrombozytenproteinen verbunden sind, die gemeinsam mit anderen genetisch bedingten Hämostasestörungen wie dem von-Willebrand-Jürgens-Syndrom Typ 1 ver -erbt werden. Folglich kann der Phänotyp einer leichten Blutung bei einigen Patienten multi-faktoriell sein und als komplexes Merkmal angesehen werden.

Keywords

Platelet dysfunction

Schlüsselwörter

Thrombozytendysfunktion

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