The Role of Claudin Variants in the Formation of Kidney Stones
Bibliographic record
Abstract
Background: Genetic risk factors contribute to the formation of calcium-based kidney stones. The majority of calcium is reabsorbed via paracellular transport through tight junctions along the human nephron epithelium where Claudin proteins are expressed. Claudins determine the selectivity and permeability of different nephron segments. Studies have shown that CLDN gene sequence variants are associated with kidney stones. I hypothesize that sequence variants in Claudin genes that regulate paracellular renal transport of calcium. will be associated with the formation of kidney stones. Methods: Patient DNA was analyzed by Fluidigm Next Generation Sequencing and confirmed by sanger sequencing. Rare variants (MAF<1%) were compared to the gnomAD database. In silico prediction software was used to predict the impact of the amino acid change. Human claudin variants were generated by site-directed mutagenesis and cloned into a mammalian expression vector, pEGFP. Immunofluorescence was performed on HEK293 cells that were transiently transfected with both variant and WT sequences. Results: Ninety adult patients (45 females, 45 males) with recurrent calcium-based kidney stones were recruited from one urologist’s kidney stone clinic. Seventy-two percent (65/90) of the patients self-defined as Canadian-European. Sixty-two percent (56/90) of the patients presented with the first kidney stone less than 40 years of age. Four novel heterozygous missense variants were identified in the following: CLDN11 S157F, CLDN16 K29E, CLDN17 A94V, and CLDN18 H212D. Nine rare variants include CLDN4 A82T, CLDN4 A113T, CLDN7 V55I, CLDN8 A94V, CLDN8 M97T, CLDN12 M98V, CLDN23 A90T, and CLDN24 V97I. CLDN4 A82T, CLDN8 A94V, CLDN11 S157F, and CLDN17 A94V are predicted to be deleterious. HEK293 cells were transiently transfected with CLDN4 A82T and the mutant protein was unable to localize to the tight junction, unlike the WT CLDN4 protein which did co-localize with ZO-1 by immunofluorescence as expected (n=3 independent experiments). Other claudin variants are under evaluation. Conclusions: The rare heterozygous variant, CLDN4 A82T is located at the second transmembrane domain and predicted to be deleterious. Functional analysis showed that CLDN4 A82T has an impact on the localization of the protein to the tight junction. Funding: Private Foundation Support
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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 | 0.001 | 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 | 0.001 |
| 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".