Investigating the pathogenicity of the recessive <i>HNF1A</i> p.A251T variant in monogenic diabetes using iPSC-derived beta-like cells
Bibliographic record
Abstract
Abstract Monogenic diabetes, formerly called Maturity-Onset Diabetes of the Young (MODY), involves single-gene mutations, typically with dominant inheritance, and has been associated with variants in 14 genes. Among these, HNF1A mutations are the most common, and their diagnosis allows the use of alternative therapies, including sulfonylureas. In an earlier study, we described a variant displaying recessive transmission, p.A251T (Misra, S et al, Diabetes Care , 2020). Initial functional studies revealed only a modest impact on protein function. We extend these earlier in vitro studies to demonstrate that beta-like cells derived from pluripotent stem cells from variant carriers show impaired differentiation into insulin-positive cells, whereas differentiation into alpha cells is significantly enhanced. Additionally, mutant cells showed impaired glucose-stimulated insulin secretion but partially preserved responsiveness to treatment with sulfonylureas. Our study provides proof of principle for the utility of using patient-derived stem cells as a platform to assess the pathogenicity of HNF1A variants, and to explore potential treatment strategies.
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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 | 0.001 | 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 | 0.001 |
| 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".