A multimorphic variant in ThPOK causes a novel human disease characterized by T cell abnormalities, immunodysregulation, allergy, and fibrosis
Bibliographic record
Abstract
ThPOK is best known as a regulator of CD4+ T cell lineage commitment, although it was initially cloned as a suppressor of collagen expression in the skin. The role of ThPOK has not been formally established in humans since individuals with damaging variants in ThPOK have not yet been identified. Here, we report the first case of a human with a damaging heterozygous de novo variant in ThPOK causing a syndrome encompassing CD4+ T cell deficiency, allergy, fibroinflammatory interstitial lung disease, developmental delay, and growth failure. The patient variant, ThPOK K360N, exhibited abnormal multimorphic activity, including interfering with ThPOK WT in regulating gene regulation (antimorph). Protein-DNA interaction assays showed inability of ThPOK K360N to bind to wild-type consensus sequences (amorph) and revealed a novel DNA-binding specificity (neomorph). Single-cell RNA sequencing of peripheral blood revealed potential developmental defects in maturation and activation of CD4+ and CD8+ T cells (hypomorph). To establish causality, we recapitulated the observed cellular defects in lentivirally transduced healthy control T cells and pulmonary fibroblasts. Transcriptomic analysis showed that T cells transduced with ThPOK K360N lacked the upregulation of activation, proliferation, and functional pathways observed in ThPOKWT-transduced cells. When overexpressed in healthy control fibroblasts, ThPOK K360N significantly increased the expression of pro-fibrotic genes implicated in pulmonary fibrosis, indicating a defect in regulating collagen expression. This novel human disease caused by a multimorphic variant in ThPOK confirms its role in CD4+ T cell development in an intact human context, while also revealing an unanticipated role for ThPOK in T cell function and the regulation of fibrotic pathways in fibroblasts.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 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".