Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 97, Issue 6, Pages 2803-2808Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.050582097
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- NHLBI NIH HHS [R37 HL042846, R01 HL042846, HL-50545, HL-42846, R01 HL050545-10, R01 HL050545] Funding Source: Medline
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The human Bernard-Soulier syndrome is an autosomal recessive disorder of platelet dysfunction presenting with mild thrombocytopenia, circulating giant platelets and a bleeding phenotype, The bleeding in patients with the Bernard-Soulier syndrome is disproportionately more severe than suggested by the reduced platelet count and is explained by a defect in primary hemostasis owing to the absence of the platelet glycoprotein (GP) Ib-IX-V membrane receptor. However, the molecular basis for the giant platelet phenotype and thrombocytopenia have remained unresolved but assumed to be linked to an absent receptor complex. We have disrupted the gene encoding the a-subunit of mouse CP Ib-IX-V (GP Ib alpha) and describe a murine model recapitulating the hallmark characteristics of the human Bernard-Soulier syndrome. The results demonstrate a direct link between expression of a CP Ib-IX-V complex and normal megakaryocytopoiesis and platelet morphogenesis, Moreover, using transgenic technology the murine Bernard-Soulier phenotype was rescued by expression of a human CP Ib alpha subunit on the surface of circulating mouse platelets. Thus, an in vivo model is defined for analysis of the human GP Ib-IX-V receptor and its role in the processes performed exclusively by megakaryocytes and platelets.
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