The link between heparan sulfate and hereditary bone disease: finding a function for the EXT family of putative tumor suppressor proteins
Bibliographic record
Abstract
Although genetic linkage analysis is a vital tool for identifying disease genes, further study is often hindered by the lack of a known function for the corresponding gene products. In the case of hereditary multiple exostoses (HME), a dominantly inherited genetic disorder characterized by the formation of multiple cartilaginous tumors, extensive genetic analyses of affected families linked HME to mutations in two members of a novel family of putative tumor suppressor genes, EXT1 and EXT2. The biological function of the corresponding proteins, exostosin-1 (EXT1) and exostosin-2 (EXT2), has emerged in part by way of a serendipitous discovery made in the study of herpes simplex virology, which revealed that the pathogenesis of HME is linked to a defect in heparan sulfate (HS) biosynthesis. Biochemical analysis shows that EXT1 and EXT2 are type II transmembrane glycoproteins and form a Golgi-localized hetero-oligomeric complex that catalyzes the polymerization of HS. In this Perspective we will review the identification and characterization of the EXT family, with a particular focus on the biology of the EXT proteins in vivo, and we will explore their possible role(s) in both normal bone development and the formation of exostoses. Hereditary multiple exostoses Hereditary multiple exostoses (HME), an autosomal dominant bone disorder, is the most common type of benign bone tumor, with an estimated occurrence of 1 in 50,000‐100,000 in Western populations. It is
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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) | 0.001 | 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".