The X‐Linked Intellectual Disability Gene, <scp><i>ZDHHC9</i></scp>, Is Important for Oligodendrocyte Subtype Determination and Myelination
Bibliographic record
Abstract
Two percent of patients with X-linked intellectual disability (XLID) exhibit loss-of-function mutations in the enzyme, ZDHHC9. One of the main anatomical deficits observed in these patients is a decrease in corpus callosum volume and a concurrent disruption in white matter integrity. In this study, we demonstrate that deletion of Zdhhc9 in mice disrupts the balance of mature oligodendrocyte subtypes within the corpus callosum. While overall mature oligodendrocyte numbers are unchanged, there is a marked increase in MOL5/6 cells that are enriched in genes associated with cell adhesion and synapses, and a concomitant decrease in MOL2/3 cells that are enriched in genes associated with myelination. In line with this, we observed a decrease in the density of myelinated axons and disruptions in myelin compaction in the corpus callosum of Zdhhc9 knockout mice. RNA sequencing and proteomic analysis further revealed a reduction in genes and proteins essential for lipid metabolism, cholesterol synthesis, gene expression, and myelin compaction, offering insights into the underlying mechanisms of the pathology. These findings reveal a previously underappreciated and fundamental role for ZDHHC9 and protein palmitoylation in regulating oligodendrocyte subtype determination and myelinogenesis, offering mechanistic insights into the deficits observed in white matter volume in patients with mutations in ZDHHC9.
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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 | 0.002 |
| 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".