The amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)‐associated C9ORF72 r(GGGGCC)n hexanucleotide repeat forms extremely stable uni‐and multi‐molecular RNA G‐quadruplex structures
Bibliographic record
Abstract
G‐rich nucleic acids in promoters, telomere repeats, immunoglobulin class switch motifs, and fragile X repeats can form G‐quadruplex structures. Quadruplexes can affect promoter activity, splicing and neurite mRNA targeting. Amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrig's disease, and frontotemporal dementia (FTD) were recently shown to be caused by expansion of a G‐rich (GGGGCC)•(CCCCGG) hexanucleotide repeat in the C9ORF72 gene and these mutant transcripts can aggregate in nuclear foci possibly sequestering repeat‐binding proteins. Here we demonstrate that the (GGGGCC)n RNA forms extremely stable uni‐ and multi‐molecular parallel G‐quadruplex structures, whose formation is influenced by repeat length. Furthermore, MBNL1, a structure‐specific splicing factor that is sequestered in myotonic dystrophy type 1 patients by binding to expanded CUG RNA repeats, does not bind the ALS‐FTD RNA hexanucleotide repeat, while the ASF/SF2 splicing factor can bind the repeat. These observations may shed light on the normal (GGGGCC)•(CCCCGG) repeat function in C9ORF72, its interacting partners, and upon pathogenic roles the expanded repeat may have in ALS‐FTD.
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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) | 0.000 | 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) | 0.002 | 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".