The Cellular and Molecular Mechanisms of Neutropenia in Barth Syndrome
Bibliographic record
Abstract
Abstract Abstract 1105 Barth syndrome (BTHS) is a rare, X-linked recessive disease characterized by progressive cardiomyopathy and neutropenia with life-threatening bacterial infections. BTHS is attributable to loss-of-function mutations in the tafazzin gene, TAZ, a phospholipid acyltransferase localized to the mitochondrial membrane and involved in remodeling cardiolipin. BTHS children exhibit reduced blood levels of total cardiolipin; however, the molecular and cellular mechanisms of BTHS remain largely unknown. We developed a model of BTHS by transfecting human HL60 myeloid progenitor cells with TAZ-specific shRNAs. Results demonstrated a significant down-regulation in the TAZ gene expression, mimicking naturally-occurring truncation mutations. FACS analyses of cells with TAZ-specific but not scrambled shRNAs demonstrated nearly two-fold increase in proportion of annexin-V positive cells and significantly increased dissipation of mitochondrial membrane potential (MMP) as determined by DIOC6-staining. Similar pro-apoptotic effects were observed in U937 myeloid progenitors, but not in Jurkat or Ramos human lymphoid cell lines. Further studies revealed aberrant release of cytochrome c from mitochondria and significantly elevated levels of activated caspase-3 in response to TAZ knock-down. Treatment with caspase-specific inhibitor zVAD-fmk reduced apoptosis to near-normal levels. FACS analysis utilizing cryopreserved bone marrow cells from a BTHS patient showed evidence of accelerated apoptosis compared to corresponding cells from a healthy volunteer. Importantly, human myeloid progenitor cells and cardiomyoblasts/cardiomyocytes depend heavily on mitochondria, which may explain why the loss of mitochondrial protein tafazzin has more severe effects on these specific tissues in BTHS resulting in neutropenia and cardiomyopathy. These data suggest that neutropenia in BTHS patients is attributable to increased dissipation of MMP, aberrant release of cytochrome c, activation of caspase-3 and accelerated apoptosis, and that this defect can be partially restored in vitro by treatment with caspase-specific inhibitors. Further studies should evaluate the TAZ–regulated mitochondrial apoptosis pathway using primary cells from BTHS patients. Disclosures: Aprikyan: Barth Syndrome Foundation: Research Funding. Dale:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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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 | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 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) | 0.001 | 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".