A novel variant in MFN2 linked to a lethal disorder of neonatal onset
Bibliographic record
Abstract
Abstract Pathogenic variants in the mitochondrial fusion protein Mitofusin2 typically cause axonal Charcot-Marie-Tooth disease type 2A (CMT2A), a progressively degenerative peripheral neuropathy. Here, we present three siblings with a lethal disorder of neonatal onset who carried a novel homozygous MFN2 variant R334K, which was predicted to be likely pathogenic. Given the severe clinical presentation, which is atypical of MFN2 variants, further functional investigations were warranted to confirm the pathogenicity of the R334K variant. Characterization of patient fibroblasts revealed severe disruptions in all MFN2-related functions assayed, including mitochondrial fragmentation, altered mito-ER contacts, decreased mtDNA copy number and size, increased lipid droplet abundance, and reduced mitochondrial respiration. We also observed reduced Complex I activity, which is noted in cells lacking MFN2, but is not typical of pathogenic MFN2 variants that cause CMT2A. Notably, re-expression of MFN2 R334K in MFN2 knockout cells was unable to rescue mitochondrial fragmentation and the Complex I deficiencies, confirming that the R334K variant is causative of these cellular phenotypes. Furthermore, disease modelling in Drosophila melanogaster demonstrated functional deficiencies of the R334K variant in vivo. Together, these findings confirm that the MFN2 R334K is a novel pathogenic variant causing severe fatal neonatal disease. Finally, we show that pharmacological activation of the integrated stress response rescues the defects caused by MFN2 R334K, offering a potential therapeutic avenue for MFN2 pathology.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
| 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 | 0.001 |
| Research integrity | 0.001 | 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".