Genetic Risk of Axonal Neuropathy Following Infection
Bibliographic record
Abstract
Abstract Background Why some individuals experience severe neuropathy following infection is unknown. Nucleocytoplasmic trafficking (NCT) is an essential process in nucleated cells, and its disruption has been implicated in many neurodegenerative conditions including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Methods We performed genomic and clinical studies in 24 individuals from 12 families with acute onset axonal neuropathy. Genetic variants were characterized by thermal stability and enzymatic assays using recombinantly expressed protein. Protein localization was determined in patient fibroblasts using immunofluorescence following heat or oxidative stress. A humanized Drosophila model was generated to determine the effect of stress on in vivo function. Results We identified deleterious biallelic variants in human RCC1 , encoding a GTP exchange factor essential in maintaining Ran GTPase-dependent NCT function. Clinical presentations ranged from a rapidly progressive, fatal axonal neuropathy with encephalopathy to a mild motor neuropathy resulting in impaired walking. In most patients (n=22/24), neurological presentation was secondary to infection, resulting in prior diagnosis of Guillain-Barré syndrome (GBS) in 13. The efficiency of cellular Ran GDP-GTP exchange and the thermal stability of Rcc1 protein was reduced by disease-associated variants. Heat shock or oxidative stress revealed defects in Ran nuclear localization, impaired NCT, and TDP-43 mislocalization in patient fibroblasts. Disease associated variants were unable to rescue the thermosensitive phenotype of a rcc1 deficient hamster cell line. RCC1 Drosophila models revealed a fatal intolerance to oxidative stress. Conclusion We describe a novel autosomal recessive acute onset axonal neuropathy triggered by infection caused by biallelic RCC1 variants, which mimics GBS and has important mechanistic overlap with ALS.
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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 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.002 |
| 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".