Glycine Supplementation – A Novel Therapeutic Strategy for Congenital Sideroblastic Anemia.
Bibliographic record
Abstract
Abstract Abstract 2087 Congenital sideroblastic anemias (CSA) are inherited diseases, characterized by ineffective haematopoiesis, typically severe microcytic anemia and bone marrow sideroblasts representing excess iron deposition in the mitochondria of the erythroid precursors. More than 40% of CSA cases are attributed to mutations in the X-linked gene ALAS2. ALAS2 encodes the mitochondrial enzyme aminolevulinic acid synthase-2, which utilizes glycine to form 5-aminolevulinic acid (5-ALA), a crucial precursor in heme synthesis. Another gene, SLC25A38, has recently been implicated in the abnormal heme development noted in CSA. The function of the SLC25A38 protein product is uncertain, although it is thought to be an erythroid specific mitochondrial carrier family protein, transporting glycine across mitochondrial membranes. We employed yeast and zebrafish model systems in parallel to evaluate the absence of SLC25A38 or ALAS2 on heme synthesis in vivo and identify potential therapeutic strategies. HEM1 (ALAS2 homologue) mutant yeast were completely unable to make heme, whereas heme synthesis was significantly reduced in YDL119c (SLC25A38 homologue) mutant yeast. To monitor heme synthesis, we utilized a beta-galactosidase reporter linked to Pcyc1, which is only active following binding of the yeast Hap1 transcription activator in the presence of heme. Both HEM1 and YDL119c mutant yeast showed no beta-galactosidase activity, however activity in the YDL119c mutant was returned to 30% with the addition of 5-ALA and to 40% following treatment with glycine. Microarray studies of untreated and glycine treated YDL119c mutant yeast revealed increased expression of genes required to synthesize vitamin B6, a cofactor for the Hem1 enzyme in yeast and humans. Morpholino (MO)-mediated knockdown of the zebrafish homologues of SLC25A38 (slc25a38a and slc25a38b) or alas2 correlated with decreased hemoglobin levels by o-dianisidine staining and increased embryonic malformation and mortality. 5-ALA treatment either by addition to the egg water or by injection into the yolk failed to restore hemoglobinization in alas2 morphant embryos. By contrast, the addition of glycine to the egg water resulted in upregulation of hemoglobin to near normal levels in the majority of slc25a38a/b double morphant embryos. Our study demonstrates conserved heme synthesis pathways through evolution across species and further supports the contention that SLC25A38 functions as a glycine transporter. Most significantly, glycine supplementation emerged as an effective therapeutic strategy to restore heme synthesis in CSA caused by SLC25A38 deficiency, providing the rationale to support use of glycine in a clinical trial that is under development for these patients. Disclosures: McMaster: DeNovaMed: Equity Ownership.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".