Mutations in the β-tubulin TUBB impair ciliogenesis and are associated with ciliopathy-like phenotypes
Bibliographic record
Abstract
Tubulinopathies and neurodevelopmental ciliopathies are two groups of genetic disorders that cause structural brain malformations. Tubulinopathies result from mutations in tubulins, the building blocks of microtubules, most of which are dominant. Neurodevelopmental ciliopathies are mostly recessive disorders caused by defects in the primary cilium, an organelle that regulates key signaling pathways during brain development. Although more than 40 genes have been associated with neurodevelopmental ciliopathies, many patients still lack a known genetic cause. Here, we present a de novo heterozygous missense variant (p.G308S) in Tubulin Beta Class I (TUBB) identified in a patient showing features of both ciliopathy and tubulinopathy. While microtubules are essential for primary cilia formation and function, an association between tubulin mutations and neurodevelopmental ciliopathies has not been established. Using patient-derived cells and gene-edited isogenic cell lines, we show that the identified variant impairs the early stages of cilia formation by altering microtubule dynamics and structure. Consistent with this, mice carrying the variant display decreased ciliation in the cerebellum and kidney. Furthermore, we demonstrate that the disease mechanism is not haploinsufficiency and that other patient mutations in TUBB affect cilia formation, putting forward defective ciliogenesis as a contributing pathogenic factor in a subset of tubulinopathy patients.
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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 | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".