Identification of a dysfunctional missense single nucleotide variant of human adenylyl cyclase VI
Bibliographic record
Abstract
Genetic variants have been described for a range of G protein-coupled receptors (as well as for G proteins) linked to adenylyl cyclase. Furthermore, expression of these variants resulted in alterations in receptor-mediated activation of adenylyl cyclase, as well as alterations in more "downstream" effector pathways mediated by cyclic adenosine monophosphate. However, the identification of dysfunctional variants of adenylyl cyclase has been far more limited. Screening a region of the molecule that we recently demonstrated to be critical in regulation of enzyme activity, we have identified a missense single-nucleotide variant at amino acid 674 of human adenylyl cyclase isoform VI. In a population of 286 healthy white subjects, this variant has an allelic frequency of 3.1% (although 0/90 nonwhite subjects had this variant). Expression of this variant of adenylyl cyclase VI (whether expressed as the S674 human adenylyl cyclase VI [ADCY6] or the S686 ADCY6 rat analog) is characterized by a significant decrease in stimulated adenylyl cyclase activity (forskolin-stimulated activity of the S674 human ADCY6 variant was decreased to 56% +/- 6% of the activity of the A674 variant [mean +/- SEM]; n = 9; P = .004). Furthermore, subjects with the S674 variant demonstrated a significantly higher lymphocyte count (2.68 +/- 4.13 x 10(3)/mm3 versus 1.90 +/- 0.72 x 10(3)/mm3, P = .019). Paralleling this phenotype, expression of the variant was associated with attenuation of the forskolin-mediated reduction in cell growth rate to 64% +/- 5% of the effect seen with expression of the wild-type ADCY6 (n = 4; P = .001). In summary, these data demonstrate an unappreciated variant of adenylyl cyclase isoform VI that has a functional impact on both enzyme activity and cyclic adenosine monophosphate-mediated regulation of cell growth.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.002 | 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".