Abstract 054: Mutations In Pde3a Explain Mendelian Hypertension With Brachydactyly
Bibliographic record
Abstract
We identified Mendelian type E brachydactyly (BDE) with hypertension in six different families from Turkey, America, France, Canada and South Africa. The two phenotypes, hypertension and BDE, invariably coincide. The blood pressure in affected individuals increases with increasing age, the mean arterial blood pressure at 50 years exceeds 150 mm Hg, resulting in stroke. Earlier we suggested that a chromosomal rearrangement on 12p could be responsible. We now used whole-genome sequencing and discovered six different so far unknown missense mutations in the gene encoding PDE3A. The mutations are not identical, but adjacent to each other. Each is responsible for an amino acid substitution in a conserved portion of the protein. The mutations were not present in any non-affected family members, in more than 200 additional controls, and not found in the “1000 genome” project. We performed in vitro cell transfections and found that mutated PDE3A showed gain-of-function with increased cAMP hydrolysis. Mesenchymal stromal cell-derived vascular smooth muscle cells and chondrocytes gave insight into the molecular pathogenesis; PDE3A and vasodilator-stimulated phosphoprotein (VASP) were differently phosphorylated and parathyroid hormone-related peptide (PTHrP) was dysregulated. Our preliminary results reveal that the mutated PDE3A enzymes show gain-of-function with increased cAMP hydrolysis and sensitivity to cGMP inhibition. We suggest that the mutations are responsible for both phenotypes. This Mendelian hypertension is the first that is not attributable to increased sodium reabsorption in the distal nephron.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 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".