Identification of a Novel apoB Variant in a Family Exhibiting Hypocholesterolemia: Mechanistic Insights
Bibliographic record
Abstract
Familial hypobetalipoproteinemia (FHBL) is a rare autosomal codominant disorder. FHBL is often caused by a defect in apoB production that is required for lipoprotein formation. Here we identified three family members that exhibited very low circulating cholesterol levels. Analyses of their plasma lipid profiles revealed that the affected individuals have low levels of cholesterol and LDL-cholesterol (LDLc) lipoproteins, with no difference in lipoprotein particle size. Sequencing of the APOB gene revealed a single heterozygote deletion of an adenosine in exon 3 at the nucleotide position 1268 in all affected members. This deletion introduces a reading frame shift at glutamine 380 resulting in a stop codon at position 397. This C-terminally truncated apoB, called apoB9, is a variant spanning ~9% of the full-length protein. Upon expression of apoB9 in human hepatocyte IHH cells, the protein was detected intracellularly but it did not exit the endoplasmic reticulum and hence was not secreted into the media. Molecular modeling revealed that apoB9 lacks the βA- and βB-sheets that are required for lipid particle formation, which can explain the absence of apoB9 secretion and the low levels of plasma apoB in the affected family members, likely modifying their risk of developing CVD.
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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 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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".