Characterization of the benign mutations, R247W and R249W, associated with B-hexosaminidase A pseudodeficiency
Bibliographic record
Abstract
Deficient activity of $\\beta$-hexosaminidase A (Hex A), resulting from mutations in the HEX4 gene, typically causes Tay-Sachs disease. However, healthy individuals lacking Hex A activity against synthetic substrates (i.e. individuals who are pseudodeficient) have been described. Most of these individuals have a C739T (R247W) mutation in compound heterozygosity with a Tay-Sachs disease-causing allele. We identified a second benign mutation, C745T (R249W) in a pseudodeficient subject and showed that it accounted for approximately 6% (4/63) of enzyme-defined non-Jewish Tay-Sachs disease carriers. Taken together, the two benign mutations accounted for approximately 38% of non-Jewish enzyme-defined carriers, making their identification an important component of Tay-Sachs disease prevention programs. To confirm the relationship between benign mutations and Hex A pseudodeficiency and to determine how the benign mutations reduce Hex A activity, each of the benign mutations and other mutations associated with infantile, juvenile, and adult-onset forms of Gm2 gangliosidosis were transiently expressed as Hex S $(\\alpha\\alpha)$ and Hex A $(\\alpha\\beta)$ in Cos-7 cells. The benign mutations decreased the expressed Hex A and Hex S activities toward the synthetic substrate 4-methylumbelliferyl-6-sulfo-$\\beta$-N-acetylglucosaminide (4-MUGS) by 60 to 80%, indicating they are the primary cause of Hex A pseudodeficiency. Western blot analysis showed that the benign mutations reduced enzymatic activity by reducing the $\\alpha$-subunit protein level. No change in Hex A heat sensitivity, catalytic activity, or specificity toward 4-MUG and 4-MUGS, were detected in the studies. The effects of benign mutations on Hex A were further analysed in fibroblasts, and during transient expression, using pulse-chase metabolic labelling. These studies showed that (1) the benign mutations reduced the $\\alpha$-subunit protein by affecting its stability in vivo, not by affecting the processing of the $\\alpha$-subunit, ie. phosphorylation, targeting, or secretion, and (2) these benign mutations could be readily differentiated from disease-causing mutations using a transient expression system.
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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) | 0.001 | 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".