Recessive Variants in the Intergenic NOS1AP-C1orf226 Locus Cause Monogenic Kidney Disease
Bibliographic record
Abstract
Background: An accurate expression landscape of disease genes is crucial to enable precise genetic diagnoses. Canonical NOS1AP, encoding nitric oxide synthase 1 (NOS1) adaptor protein, is known to regulate hippocampal neuronal functions through C-terminal interactions with the enzyme NOS1 (Jaffrey Neuron 1998; Zhu Nat Med 2014). We previously discovered that N-terminal variants in NOS1AP cause monogenic nephrotic syndrome (NS) in humans and mice (Majmundar Sci Adv 2021). However, the role of the NOS1AP C-terminus in NS pathogenesis was unclear. Methods: Transcriptomics and proteomics data of human and murine kidney samples were evaluated. Exome sequencing was performed in human NS subjects. Mouse models altering the Nos1ap locus were evaluated for features of NS. Results: We, here, detected intergenic splice products of NOS1AP/Nos1ap and the neighboring open reading frame C1orf226/Gm7694 as the predominant isoform in both human and mouse kidney tissue in contrast to brain tissue. In this isoform, the canonical C-terminal NOS1-binding domain is replaced by C1orf226 or Gm7694, respectively. In line with our previously published Nos1ap-deficient mice, exclusive disruption of the intergenic product in Gm7694-/- mice similarly resulted in NS features including albuminuria, podocyte foot process effacement, and glomerular basement membrane thickening. We, next, evaluated whether recessive variants exclusively impacting the intergenic splice form can be detected in NS patients. For this, we reanalyzed NS exome sequencing data and thereby identified a likely pathogenic NOS1AP-C1orf226 essential splice site variant (c.1258+1G>C) in a patient with congenital NS. Of note, this variant was initially misclassified as benign due to annotation based on the canonical transcript (c.1259G>C, p.G420A). Conclusion: Mendelian variants impacting an intergenic product in the NOS1AP-C1orf226 locus cause NS, suggesting that, unlike in the brain, NOS1AP functions in the kidney through NOS1-independent mechanisms. Moreover, this highlights the importance of understanding tissue-specific splicing to facilitate discovery and clinical diagnosis of Mendelian disorders. Funding: NIDDK Support, 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 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".