Identification and Characterization of an Activating F229V Substitution in the V2 Vasopressin Receptor in an Infant with NSIAD
Bibliographic record
Abstract
Gain-of-function mutations in the gene encoding the V2 vasopressin receptor (V2R) cause nephrogenic syndrome of inappropriate antidiuresis. To date, reported mutations lead to the substitution of arginine 137 by either a cysteine or leucine (R137C/L). Here, we describe a 3-month-old hyponatremic infant found to have a phenylalanine 229 to valine (F229V) substitution in V2R. Characterization of this substitution in vitro revealed that it leads to high constitutive activity of the receptor, compatible with spontaneous antidiuresis. In contrast to R137C/L mutant receptors, F229V receptors do not undergo spontaneous desensitization, which results in sustained, high basal activity. Notably, the V2R-selective inverse agonists tolvaptan and satavaptan completely silenced the constitutive signaling activity of the F229V mutant receptor, indicating that this substitution does not lock the receptor in an irreversible active state. Thus, inverse agonists might prove to be effective therapies for treating patients with this or other spontaneously activating mutations that do not lock the V2R in its active state. These results emphasize the importance of genetic testing and the functional characterization of mutant receptors for patients with nephrogenic syndrome of inappropriate antidiuresis because the results might inform treatment decisions.
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How this classification was reachedexpand
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 | 0.000 |
| 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) | 0.000 | 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 teacher head, 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".