Neurodevelopmental disorder mutations in the exchange factor DENN/MADD disrupt activation of Rab GTPases
Bibliographic record
Abstract
DENN/MADD (mitogen-activated protein kinase-activating death domain), a differentially expressed in normal and neoplastic cells (DENN) domain-containing protein functions in membrane trafficking. DENN domain-bearing proteins have guanine nucleotide exchange factor activity toward Rab GTPases. Here, we identify Rab GTPase substrates for DENN/MADD using a cell-based assay involving DENN domain-mediated recruitment of Rab substrates to mitochondria. We confirmed known interactions of DENN/MADD with Rab3A, Rab3B, Rab3C, Rab3D, and Rab27B and identified four new potential substrates, Rab8B, Rab15, Rab26, and Rab37, results confirmed with biochemical experiments. Mutations in the DENN domain of DENN/MADD result in diverse pathophysiological manifestations, ranging from predominant neurological dysfunction to a multisystem disorder. Structural analysis using AlphaFold suggested that these mutations affect DENN/MADD's interaction with Rab GTPases. Introducing such mutations into DENN/MADD's DENN domain influenced the mitochondrial recruitment of Rabs. This study identifies new DENN/MADD protein interactions and cellular pathways, the disruption of which results in human disorders.
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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 | 0.000 |
| 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".