Dysregulation of C10orf55 Expression in Megakaryocytic Cell Lineage From Quebec Platelet Disorder Individuals
Bibliographic record
Abstract
Abstract 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. Disclosures: No relevant conflicts of interest to declare.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.006 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".