Uncovering functional insights into human pathogenic variants in <i>CDK19</i> using Drosophila models
Bibliographic record
Abstract
Abstract Heterozygous missense variants in CDK19 have been found in patients diagnosed with Developmental and epileptic encephalopathy-87 (DEE87) who present with global developmental delay, intellectual disability and other muscular and neurological deficiencies. Two missense variants in CDK19, Y32H and T196A , were first proposed to be dominant negative in nature based on experiments in a Drosophila model. Subsequently, another group proposed that Y32H is a gain of function based on elevated kinase activity. We present a detailed evaluation of the activity and functionality of these dominant variants in several contexts in fly models of DEE-87 in which endogenous cdk8 , the fly ortholog of human CDK8 and CDK19 , is knocked down while we overexpressed the human genes. Depletion of Drosophila cdk8 causes thicker muscle myofibrils, fused mitochondria, and climbing defects. The expression of human CDK19 WT in a fly cdk8-RNAi background rescues these defects, highlighting functional conservation. To investigate functional differences between the variants, we compared effects of variants to expression of wildtype CDK19. Ubiquitous expression of Y32H can rescue the cdk8 knockdown phenotype through a gain of function compensatory effect, while T196A is unable to do so through a possible reduction in kinase activity. We found that supplementation of the antioxidant drug, N-acetylcysteine amide (NACA), rescues phenotypes of only the T196A adult flies, illustrating a divergence in variant functionality. Our studies in flies allowed us to assay these variants in numerous contexts to gain further insight into their mechanism and obtain translational knowledge to apply back to human health.
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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) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".