Ubiquitin ligase defect by <i>DCAF8</i> mutation causes HMSN2 with giant axons
Bibliographic record
Abstract
OBJECTIVE: To identify the genetic cause of axonal hereditary motor and sensory neuropathy (HMSN2) with infrequent giant axons. METHODS: We studied 11 members of a previously described HMSN2 family with infrequent giant axons and variable cardiomyopathy. Whole-exome sequencing (WES) was performed on 2 affected persons and 1 unaffected person. Sanger sequencing was utilized to confirm the identified novel variant tracking with the affected status. Linkage analysis and haplotype mapping were obtained to confirm the causal nature of the identified variant. Cotransfection of HEK293 cells and co-immunoprecipitation assay were performed to assess the impact of the identified mutant protein in the implicated ubiquitin ligase pathway. RESULTS: Giant axons with neurofilament accumulations were found in 3 affected persons who had undergone nerve biopsy evaluations. Six novel variants were identified by WES, but only DCAF8 p.R317C tracked with affected status within the family. Linkage and haplotype analysis using microsatellite markers supported this variant as causal. The mutation is within the DCAF8 WD repeat region critical for its binding to DDB1. Functional analysis shows DCAF8 p.R317C reduces the association of DCAF8 and DDB1, which is important in Cul4-ubiquitin E3 function. CONCLUSIONS: Our results indicate that DCAF8 p.R317C mutation is responsible for this specific variety of HMSN2 with infrequent giant axons and mild cardiomyopathy. This mutation results in decreased DDB1-DCAF8 association, leading to an E3 ubiquitin ligase defect that is likely associated with neurofilament degradation.
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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".