Insertions/Deletions Upstream of ZHX2 in Hispanic Patients Cause Non-HIV Collapsing Glomerulopathy (CG) Through Podocyte ZHX2 Upregulation
Bibliographic record
Abstract
Background: We previously published 8 Hispanic patients with COVID-19 related CG and Insertions/Deletions (InDels) upstream of ZHX2, including 3 shared InDels (Del Nogal Avila M et al JCI Insight 2023). We also showed that sera from over 30 Hispanic patients with CG induce glomerular collapse when injected into Sprague Dawley (SD) rats inbred in Mexico City (Avila-Casado et al KI 2004). We replicated these InDels individually using CRISPR/Cas9 editing of iPS cell lines. We also studied if Parvovirus infection in rats predisposes to Zhx2 upregulation. Methods: See Below Results: Using CRISPR/Cas9, TATAAA at Chr8 122,720,313 - 122,720,318 was deleted from iPS cells and differences in Zhx2 mRNA and protein expression studied between the parent and mutated cell lines. We noted 4.85 + 0.67 fold upregulation of Zhx2 mRNA expression (P<0.0001) and increased ZHX2 protein expression (P<0.05) in the mutant clones. Two other CRISPR/Cas9 modifications are in progress. Since human transplant recipients with Parvovirus B19 infection develop CG, we injected SD rats infected with rat Parvovirus with human sera from patients with recurrent CG. These rats developed extensive CG 10 days after injection. The rats were then re-derived to make them pathogen free, and the cleaned rats did not develop proteinuria or CG after CG serum injection. Analysis of glomerular gene expression from non-injected parvovirus infected and clean rats showed significant podocyte / glomerular Zhx2 mRNA upregulation (7.16 + 2.3 fold, P<0.01) in parvovirus infected rats. After injection of CG serum, these infected rats developed further glomerular Zhx2 mRNA upregulation (Day 6, 6.3 + 0.55, P<0.001; Day 10, 5.59 + 1.84, P<0.05) compared to control serum injected rats. Finally, podocyte specific ZHX2 overexpressing transgenic rats (Mace C et al KI 2020) with > 3-fold higher podocyte Zhx2 expression develop extensive CG when injected with Adriamycin. Conclusion: Genomic defects upstream of ZHX2 in Hispanic patients with CG induce ZHX2 upregulation, that predisposes to the development of CG. These defects are likely be prevalent worldwide except for patients of West African heritage. Funding: NIDDK 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 | 0.000 |
| 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) | 0.002 | 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".