Glial Cells Missing-2 (GCM2) transactivates the calcium-sensing receptor gene: effect of a dominant-negative GCM2 mutant associated with autosomal dominant hypoparathyroidism
Bibliographic record
Abstract
Glial cells missing-2 (GCM2) is a transcription factor expressed in the parathyroid hormone (PTH)-secreting cells of the parathyroid gland and is essential for their development. Thus far, downstream targets of GCM2 have not been identified. Here, we show that both promoters (P1 and P2) of the calcium-sensing receptor (CASR) gene, a differentiation marker for the parathyroid gland, are transactivated by wild-type GCM2. GCM response elements within CASR P1 (-451 to -441; relative to the transcription start site at +1) and CASR P2 (-166 to -156) were identified by mutated promoter-reporter studies as well as oligonucleotide precipitation assays. Primary hypoparathyroidism is a heterogeneous group of conditions characterized by hypocalcemia and hyperphosphatemia due to deficient PTH secretion. A few cases of familial isolated hypoparathyroidism with autosomal recessive inheritance have been identified that are caused by homozygous inactivating mutations in the GCM2 gene. We describe the GCM2 mutations in two families with hypoparathyroidism, one inherited in an autosomal recessive fashion and the other in an autosomal dominant manner. In transfection studies using a promoter-reporter construct having synthetic multimerized GCM elements in the promoter, the dominantly inherited mutant GCM2 exerted a dominant-negative effect on wild-type GCM2 activity, whereas recessively inherited mutants did not. In addition, we show that the transactivation of the CASR promoter-reporter constructs by wild-type GCM2 is completely abolished in the presence of the dominant-negative mutant GCM2.
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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 | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".