Abstract 2274

Quebec platelet disorder (QPD) is a unique and serious bleeding disorder, associated with a gain-of-function defect in fibrinolysis that leads to a delayed onset bleeding after surgery or trauma in affected individuals. It has an autosomal dominant pattern of inheritance and affected individuals typically demonstrate an extensive personal and family history of bleeding. The disorder is caused by a tandem duplication mutation of a 78-kb genomic region located on chromosome 10 that contains PLAU (the gene that encodes urokinase plasminogen activator, uPA) in addition to the gene C10orf55, a gene of unknown function that encodes a transcript with partial complementary regions to PLAU mRNA. While QPD has minimal effects on uPA in urine, plasma and many other cell types, it elevates uPA levels >100 fold in QPD platelets compared to controls, due to overexpression of PLAU during megakaryopoiesis. As C10orf55 expression is postulated to have negative regulatory effects on uPA expression, we investigated if there is evidence of C10orf55 dysregulation in QPD. TaqMan assays were utilized for quantitative real-time RT-PCR analysis of C10orf55 transcripts in QPD and control CD34+ peripheral hematopoietic progenitors, platelets, lymphoblasts and saliva buccal cells (n=4–8 control and patient subjects for each cell type). QPD platelets contained elevated levels of C10orf55 mRNA that were >130 fold higher than in control platelets (p<0.001). Whereas in the other QPD cell types that were examined, the levels of C10orf55 mRNA were within the range expected for one additional copy of this gene, based on transcript levels measured in the control cells. These data demonstrate that the tandem duplication mutation of QPD leads to megakaryocyte specific increases in C10orf55 expression that parallel the pathological changes in PLAU expression during megakaryopoiesis. Although C10orf55 has been postulated to downregulate PLAU expression, due to complementarity of its transcripts, this seems unlikely given our findings. Our study indicates that the pathogenesis of QPD involves megakaryocyte-differentiation specific dysregulation of both genes contained in the 78-kb tandem duplicated locus on chromosome 10.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.