REN p.L16del Mutation Is Associated with a Milder In Vitro and Clinical Phenotype Compared with Other Signal Peptide Mutations
Bibliographic record
Abstract
Background: Autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN) presents with hyporeninemic hypoaldosteronism, hyperkalemia, mild hypotension, acidemia and hyperuricemia leading to slowly progressive chronic kidney disease. ADTKD-REN causing mutations have been identified in all three functional renin domains: signal peptide (SP), prorenin, and mature renin. SP mutations are associated with earlier clinical presentation and faster progression than mutations in other domains. Here we report on the most prevalent p.L16del mutation in the SP and compare its phenotype with other SP mutations. Methods: We reviewed the Wake Forest Registry for individuals with the REN p.L16del mutation and their outcomes. To assess the effect on prorenin and renin synthesis and secretion, we transiently expressed wild type, p.L13Q, p.L16del, p.L16P, p.W17R and p.C20R SP mutationsin in HEK293 cells and characterized their properties. Results: Nine of 22 (41%) ADTKD-REN families in the Wake Forest REN registry have the p.L16del mutation. Clinical information was available for 33 individuals with p.L16del and 20 individuals with missense SP mutations. Age of presentation for p.L16del was 18.8±9.4 years vs 12.0±8.2 years for missense SP mutations (P=0.02). Individuals with p.L16del were more likely to present with gout (48% vs 0%, P=0.001) and less likely to present with CKD (9.5% vs 50%, p<0.01). Males with p.L16del were more likely to present with gout (78% vs 25%, P=0.02) and females with anemia (22% vs 75%,P=0.02). The average age of kidney failure for p.L16del was 54.2±11.5 (n=14) vs 51.4±11.0 for other SP mutations (n=11, P=0.538). In vitro studies showed the p.L16del was the only SP mutation that allows for at least partial (50% of the wild type) co-translational translocation, preprorenin processing and prorenin and renin secretion. Conclusion: The p.L16del variant is the most prevalent mutation causing ADTKD-REN. It is associated with milder cellular effects and correspondingly has a milder clinical presentation, though power was limited to detect differences in ESRD age. This information will help inform patients with this condition and their physicians. Funding: Private Foundation Support
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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 | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".