Recessive Mutations in POLR3B Encoding the Second Largest Subunit of Pol III Cause a Rare Hypomyelinating Leukodystrophy (P05.136)
Bibliographic record
Abstract
Objective: Search for mutations in the second largest subunit of RNA polymerase III (Pol III), POLR3B , in case negative for mutation in POLR3A . Background Leukodystrophies are a heterogeneous group of neurodegenerative disorders characterized by abnormal central nervous system white matter. It is estimated that at least 30% to 40% of patients with leukodystrophies remain without a precise diagnosis, despite extensive investigations. We recently demonstrated that mutations in POLR3A, encoding the largest subunit of RNA polymerase III (Pol III), were responsible for the majority of cases presenting with three clinically overlapping hypomyelinating leukodystrophy phenotypes. Design/Methods: We sequenced all exons, exon-intron boundaries and 39 and 59 UTR of POLR3B (NM_018082, hg19) on available genomic DNA from four 4H cases not found previously to carry POLR3A mutations. Results: We uncovered in four cases without POLR3A mutation, recessive mutations in POLR3B which codes for the second largest subunit of Pol III. All four cases were found to be compound heterozygote for mutations in POLR3B , with one missense mutation being common to all individuals. Conclusions: Mutations in genes coding for Pol III subunits are a major cause of childhood-onset hypomyelinating leukodystrophies typically characterized by prominent cerebellar dysfunction, oligodontia and hypogonadotropic hypogonadism. Supported by: Dr G Bernard received fellowship scholarships from the RMGA (Reseau de Medecine Genetique Appliquee) and FRSQ (Fonds de Recherche en Sante du Quebec). M. Tetreault received the Frederick Banting and Charles Best Doctoral scholarship from the CIHR (Canadian Institute of Health Research). This work was supported by Fondation sur les Leucodystrophies and the European Leukodystrophy Association (ELA). Disclosure: Dr. Tetreault has nothing to disclose. Dr. Choquet has nothing to disclose. Dr. Orcesi has nothing to disclose. Dr. Tonduti has nothing to disclose. Dr. Ballotin has nothing to disclose. Dr. Teichmann has nothing to disclose. Dr. Fribourg has nothing to disclose. Dr. Schiffmann has received personal compensation for activities with Amicus Therapeutics and Shire Human Genetic Therapies. Dr. Schiffmann has received research support from Shire Human Genetic Therapies, Amicus Therapeutics, and Genzyme Corporation. Dr. Brais has nothing to disclose. Dr. Vanderver has nothing to disclose. Dr. Bernard has received personal compensation for activities with Actelion Pharmaceuticals Canada Inc, Santhera, Venture in Research as a participant on advisory boards and research teams.
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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 | 0.000 |
| 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) | 0.000 | 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".