Identification and characterization of NAGLU mutations in a Sanfilippo B syndrome patient with a novel genotype (p.Y140C/p.R297X)
Bibliographic record
Abstract
Background: Sanfilippo B syndrome, or mucopolysaccharidosis type IIIB (MPS IIIB), is a rare lysosomal storage disorder resulting from mutations in NAGLU, which encodes for the enzyme α-Nacetylglucosaminidase (NAGLU). Patients afflicted with this disease experience mild somatic disease symptoms, but severe and ultimately lethal neurodegeneration. Patients often succumb to their symptoms in the first two decades of life. Sanfilippo B syndrome is a molecular heterogeneous disorder, in which nonsense and missense mutations frequently result in a genetic compound genotype, leading to the disease phenotype. Case Report: We report a novel compound heterozygous genotype (p.Y140C/p.R297X) in a Sanfilippo B patient. The level of NAGLU activity assayed from cultured skin fibroblasts was 0.6% of normal, confirming the biochemical diagnosis of Sanfilippo B syndrome. Immunoblot analysis using an anti- NAGLU antibody showed that the amount of NAGLU protein present was about 50% of normal. Conclusion: We have identified a novel genotype p.Y140C/p.R297X in a patient with Sanfilippo B syndrome that results in near zero NAGLU enzyme activity. We postulate that the nonsense mutation p.R297X produces either an unstable mRNA transcript or truncated protein that is rapidly degraded, whereas the missense mutation p.Y140C results in a stable but catalytically defective enzyme with near zero residual NAGLU activity. We conclude that the p.Y140C/p.R297X genotype is likely to result in a poor prognosis due to a detrimental biochemical phenotype.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.002 | 0.001 |
| 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".