Mutations in<i>TREM2</i>lead to pure early-onset dementia without bone cysts
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Bibliographic record
Abstract
A genome-wide screen using 382 STR markers to localize and identify the gene implicated in early-onset dementia (EOD) without bone cysts in a Lebanese family with three affected subjects was conducted. A unique locus homozygous by descent at chromosome 6p21.2 locus was identified. Candidate genes were explored by fluorescent sequencing and the effect of the identified mutation was confirmed by qualitative and quantitative RT-PCR. The genetic analysis revealed a novel deletion, c.40+3delAGG, in the 5' consensus donor splice site in intron 1 of TREM2 gene which is known to be responsible for PLOSL (Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy) also designated as Nasu-Hakola disease. In silico analysis predicted a lower strength for the novel donor splice site. Qualitative RT-PCR revealed normal transcript while quantitative RT-PCR showed over twofold down-regulation of TREM2 transcripts. The expression profile of six genes SPP1, NEDD9, FSCN, BCL3, NFKBIA and CCL2 known as disrupted in TREM2-deficient samples was studied and showed same expression profile as TREM2-mutated samples except for CCL2 which was normally regulated. The significantly-reduced expression of TREM2 in our patients and the expression profiles of the six studied genes confirm a role for TREM2 in this distinct phenotype of EOD without bone cysts. To our knowledge, this is the first report of mutations in TREM2 causing a pure dementia.
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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 | 0.001 |
| 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) | 0.000 | 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 it