Bibliographic record
Abstract
Rett syndrome (RTT; MIM# 312750) is a neurodevelopmental disorder, the second most common genetic cause of intellectual disability (ID) in girls. Rett incidence (1:10,000-15,000) accounts for 2-3% of all cases of severe ID of genetic origin and 10% of the cases of profound ID in females. RTT is caused by mutations in the X-linked Methyl CpG binding protein 2 (MECP2) gene. Globally, MECP2 mutations affect 30,000 new patients each year, including ~40/year in Canada. Over 33% of all RTT patients have mutations that change a single amino acid in the protein (missense), ~half of which occur within the methyl-CpG-binding domain (MBD), by which MeCP2 protein binds to its target genes. In this thesis, we aimed to identify the pathophysiological mechanisms by which mutations affect the protein’s function. Firstly, we identified a cryptic splice event at pre-mRNA level in a Rett syndrome girl with a synonymous de novo mutation, Gly16Gly. Secondly, we studied functional and clinical correlation of single residue substitutions in MeCP2-MBD. In particular, we highlighted the distinction at the cellular level between missense changes at methylated DNA-binding residues from other changes, which affect the structure of MeCP2-MBD and are involved in chromatin clustering and organization. We further showed that the severe functional changes results in the severe and milder functional changes result in milder phenotypes. Furthermore, we identified the functional role of post-translational modification of MeCP2 N-terminal domain (NTD) on the overall life of the protein, and simultaneously the likely etiopathological mechanism of a MeCP2-E1 isoform specific missense mutation p.Ala2Val, which has been identified in four Rett girls. Lastly, we identified MeCP2 an AT-hook1 mutation in a large consanguineous family with cognitive disability and schizophrenia, and another reported as de novo in a woman with schizophrenia, and demonstrated its effect on AT-rich DNA binding and overall chromatosome condensation.
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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 | 0.001 |
| 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".