An exon trap with proper poly-A site in the GBE1 is the common missing cause in Adult Polyglucosan Body Disease (S42.006)
Bibliographic record
Abstract
OBJECTIVE: Identify the underlying genetic cause of glycogen branching enzyme (GBE) deficiency in manifesting heterozygous patients of adult polyglucosan body disease (APBD). BACKGROUND: APBD is an autosomal recessive leukodystrophy caused by mutations in glycogen branching enzyme (GBE1). It is a late onset variant of glycogen storage disorder type-IV. Most patients are Ashkenazi-Jewish descendants, 70[percnt] of whom have homozygous GBE1 mutations. The remaining 30[percnt] are heterozygous for the p.Y329S mutation. The second mutation was not found until now in those patients in spite of whole-genome sequencing. This had raised the possibility that p.Y329S heterozygous cases were somehow ‘manifesting heterozygotes’. DESIGN/METHODS: We studied 16 APBD patients who are heterozygous for p.Y329S mutation in GBE1 with yet have unlikely low GBE activity with no other known mutation in 16 exons. RESULTS: GBE1 mRNA has been reverse transcribed and sequenced, all manifesting heterozygous patients were homozygous for c.986A>C mutation substituting tyrosine with serine. The mRNA transcript from the other allele was missing the exon 16 and 3’UTR. GBE encoded by this copy was degraded in the cell causing the further decrease of enzyme activity from 18[percnt] to 8[percnt]. Sequencing of polyA tailed mRNA revealed an exon splice site that changes last exon and 3’UTR. CONCLUSIONS: We now identified this deep-intronic mutation, which acts as a gene-trap, creating an ectopic last-exon, 3’UTR and degraded protein. This second-most common APBD mutation now explains all Ashkenazi-Jewish cases and a molecular mechanism for manifesting heterozygosis.
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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) | 0.000 | 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) | 0.003 | 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".