Quebec platelet disorder is linked to the urokinase plasminogen activator gene (PLAU) and increases expression of the linked allele in megakaryocytes

Abstract

Quebec platelet disorder (QPD) is an autosomal dominant disorder with high penetrance that is associated with increased risks for bleeding. The hallmark of QPD is a gain-of-function defect in fibrinolysis due to increased platelet content of urokinase plasminogen activator (uPA) without systemic fibrinolysis. We hypothesized that increased expression of uPA by differentiating QPD megakaryocytes is linked to PLAU. Genetic marker analyses indicated that QPD was significantly linked to a 2-Mb region on chromosome 10q containing PLAU with a maximum multipoint logarithm of the odds (LOD) score of ؉11 between markers D10S1432 and D10S1136. Analysis of PLAU by sequencing and Southern blotting excluded mutations within PLAU and its known regulatory elements as the cause of QPD. Analyses of uPA mRNA indicated that QPD distinctly increased transcript levels of the linked PLAU allele with megakaryocyte differentiation. These findings implicate a mutation in an uncharacterized cis element near PLAU as the cause of QPD.

Genetic basis of congenital platelet disorders

“…45 Sequencing of the candidate gene PLAU, which encodes uPA, did not reveal putative coding or regulatory mutations, although it was observed that there was disproportionate allelic expression in patients, suggesting a cis regulatory defect. 43 Copy number variation screening and subsequent targeted sequencing demonstrated a 78 kb tandem duplication of PLAU in patients, but not control samples. 46 The mechanisms of mild thrombocytopenia and platelet dysfunction have not yet been elucidated.…”

“…40 Quebec platelet disorder, another autosomal-dominant inherited platelet disorder with linkage to chromosome 10 (10q24), is characterized by a gain-of-function defect in fibrinolysis and increased platelet stores of urokinase plasminogen activator (uPA), which results in delayed-onset bleeding after clinical challenge. [41][42][43][44] Although platelets are structurally normal and platelet counts minimally reduced to normal, there is plasminmediated degradation of ␣-granule proteins and increased uPA released from activated platelets in Quebec platelet disorder, resulting in decreased aggregation and accelerated clot lysis. 45 Sequencing of the candidate gene PLAU, which encodes uPA, did not reveal putative coding or regulatory mutations, although it was observed that there was disproportionate allelic expression in patients, suggesting a cis regulatory defect.…”

Improving blood disorder diagnosis: reflections on the challenges

“…Pregnancy outcomes are reported to be good, with no treatments required for uncomplicated deliveries [17] 2006 Quebec platelet disorder is reported to cause a unique gain-of-function defect in fibrinolysis, from release of platelet uPA during clot formation [19]. Thromboelastography is excluded as a possible diagnostic screening test [19] 2008 Quebec platelet disorder is reported to have minimal effect on urinary uPA [24] 2009 Quebec platelet disorder is linked to PLAU (uPA gene) with increased expression of uPA, by the linked allele, during megakaryocyte differentiation [22]. uPA is demonstrated to be targeted to a-granules in the disorder [23].…”

Thrombopoietin levels in Quebec platelet disorder—Implications for the mechanism of thrombocytopenia

“…TPO levels in plasma are increased in disorders that impair megakaryocyte and platelet production, such as aplastic anemia, and are normal in thrombocytopenic disorders that do not reduce the megakaryocyte mass, including those that accelerate platelet clearance 1, 2. We postulated that a detailed analysis of TPO levels in Quebec platelet disorder (QPD) might provide insights into why platelet counts are reduced in this inherited bleeding disorder3 which is caused by a duplication mutation of PLAU , the urokinase plasminogen activator (uPA) gene 4, 5. QPD markedly and selectively increases the production of normal PLAU transcripts by the disease chromosome in megakaryocytes but not in leukocytes through unknown mechanisms,6 and this increases megakaryocyte and platelet uPA levels by more than 100‐fold 7, 8.…”