Molecular genetics of chorea-acanthocytosis
Bibliographic record
Abstract
Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder whose characteristic features include hyperkinetic movements and abnormal red blood cell morphology. The disorder shares features with Huntington's disease and McLeod syndrome (MLS), and can sometimes be difficult to distinguish clinically from the latter. In 1997, ChAc was linked to a 6-cM region on chromosome 9q21-22. A novel gene, >em>CHAC, was identified in the critical region. CHAC (now renamed VPS13A) encodes a large protein called chorein, with a yeast homologue implicated in protein sorting. In this study, all 73 exons plus flanking intronic sequence in VPS13A were screened for mutations in 83 unrelated ChAc patients. We identified 88 different VPS13A mutations in 72 probands, comprising six deletions of entire exons, 22 nonsense, 36 frameshift, 19 splice-site and five missense mutations. This disorder therefore shows substantial allelic heterogeneity: however, evidence for common inheritance of the EX70_73del mutation in four French Canadian pedigrees indicates a possible founder effect in this population. Expression of VPS13A appears to be ubiquitous, as determined by tissue-specific analysis of mRNA and chorein distribution. However, chorein expression was markedly reduced or undetectable in lymphoblasts, fibroblasts and erythrocyte membranes from 14 ChAc patients. In contrast, MLS cells showed chorein expression similar to control levels, suggesting that loss of chorein expression is a diagnostic feature of ChAc. Yeast two-hybrid analysis of six different -600 amino-acid chorein fragments was used to screen a human brain cDNA library for proteins that may interact with chorein. One fragment interacted weakly with constructs derived from transcription factor NF-κB, putative protein phosphatase PP2Cη and TAB2, a protein implicated in the mitogen-activated kinase cascade. Although exogenously expressed chorein and TAB2 did not appear to colocalise, co-immunoprecipitation experiments supported an interaction between the two proteins, suggesting an avenue for future research into chorein function.
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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 | 0.001 |
| 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) | 0.002 | 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".