A mutational hotspot in TUBB2A associated with impaired heterodimer formation and severe brain developmental disorders
Bibliographic record
Abstract
Introduction Microtubules are essential components of the neuronal cytoskeleton. The α - and β -tubulins, variably expressed in the central nervous system, play key roles in neurogenesis and brain development. Pathogenic variants in TUBB2A have recently been identified as an ultra-rare cause of pediatric neurodevelopmental disorders (NDDs). However, the neurological and behavioral manifestations, genotype–phenotype correlations, and underlying disease mechanisms remain poorly understood due to the limited number of reported families. Methods We describe a cohort of families presenting with microcephaly, global developmental delay, speech impairment, seizures and/or EEG abnormalities, movement disorders and severe behavioral disorders. Clinical assessments and brain imaging studies were conducted over a 10-year follow-up period. Genetic analysis was performed via whole-exome sequencing (WES), and structural modeling was used to investigate the functional impact of the identified variants. Results WES revealed a novel recurrent heterozygous pathogenic variant in TUBB2A (NM_001069.3:c.1172G > A; NP_001060.1:p.Arg391His), identified as the cause of disease in multiple affected individuals from unrelated families. Comparative analysis with previously reported TUBB2A de novo variants confirmed that this novel recurrent mutation affects a highly conserved Arg391 residue within the longitudinal E-site heterodimer interface. Computational modeling demonstrated that the variant disrupts α / β -tubulin heterodimer formation, impairing binding stability at this critical interaction site. Discussion Our findings expand the phenotypic and genotypic spectrum of TUBB2A -related disorders and identify Arg391 as a mutational hotspot linked to severe brain developmental disorders due to aberrant tubulin dynamics, highlighting the disruption of the α / β -tubulin heterodimer formation as the disease mechanism associated to this novel hotspot variant. These results provide new insights into disease mechanisms and offer a foundation for potential future therapeutic approaches aimed at stabilizing α / β -tubulin interactions.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".