Uncovering functional insights into human pathogenic variants in <i>CDK19</i> using Drosophila models
Bibliographic record
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 neuromuscular deficiencies. Two missense variants in CDK19, Y32H and T196A, were first proposed to be loss of function based on experiments in Drosophila models of DEE87. Subsequently, it was proposed that Y32H is a gain of function with elevated kinase activity. We present a detailed functional evaluation of these dominant missense variants in several contexts. We use fly models of DEE87 in which endogenous cdk8, the fly ortholog to human CDK8 and CDK19, is depleted through RNA interference (RNAi) while expressing the human genes. Depletion of Drosophila cdk8 causes thicker muscle myofibrils, fused mitochondria, and climbing defects. The expression of wild-type human CDK19 in a fly cdk8 knockdown background rescues these defects, highlighting functional conservation. In our assays, we used a cdk8 depleted background and individually expressed either the variant or wildtype CDK19 to compare the function of the variants relative to wild-type. We demonstrate that Y32H can rescue defects caused by cdk8 depletion, while T196A is unable to due to possible loss of function. Further, we find that supplementation of the fly diet with an antioxidant improves T196A phenotypes. Our Drosophila studies allowed us to assay these variants for further insight into their functional nature and to obtain translational knowledge that may be applied 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) | 0.000 | 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) | 0.002 | 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".