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Steroid resistant nephrotic syndrome (SRNS) – Discover and functionally characterize full-penetrance causes of SRNS

Subject Area Human Genetics
General Genetics and Functional Genome Biology
Nephrology
Term from 2021 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 461126211
 
Final Report Year 2024

Final Report Abstract

Steroid resistant nephrotic syndrome (SRNS) is the second most frequent cause of chronic kidney disease (CKD) before 25 years of age. To date, no curative treatment is available. In approximately 25% of SRNS cases, an underlying genetic cause can be detected in one of ~70 genes known to cause SRNS, with important therapeutic implications for the patient. To discover additional monogenic causes of SRNS and further decipher pathogenic mechanisms, we applied exome sequencing (ES) on DNA samples from SRNS families. We expanded the spectrum of pathogenic variants attributed to deleteriousness in already established genes and found several novel SRNS disease genes, for which we validated their candidate status. One promising candidate gene is XPNPEP2, encoding for an aminopeptidase, which plays an important role in the metabolism of kinins, a group of inflammatory and vasoactive peptides. We found 3 likely pathogenic variants in 3 separate families, and in vitro studies revealed localization of Xpnpep2 to the glomerular podocytes, where causative NS genes are predominantly expressed, as well as reduced enzymatic activity of the protein resulting from the patients’ variants in comparison to the wildtype protein. Paving the way for a therapeutic approach, we established quantitative and reproducible phenotyping in 3 mouse models of Nphs1-deficiency, which is the second most frequent cause of SRNS, to allow for sensitive detection of phenotypic improvements. We used four highly distinguishable parameters: 1. cohort survival, 2. podocyte foot process density per length of glomerular basement membrane, 3. tubular microcysts in brightfield microscopy, and 4. urinary albumin/creatinine ratios. Subsequently, we started to work on gene replacement therapy (GRT), using an adeno-associated virus as a vector for transgene delivery. Since Nphs1 is expressed in the glomerular podocyte, we studied various viral capsids using fluorescent reporters (e. g. tdTomato) to determine location of transgene expression. After optimization of targeting podocytes, the next step will be to apply the NPHS1-containing AAV in a rescue approach. In summary, ES has helped in elucidating a multitude of novel disease-causing genes in SRNS. Studying these candidate genes and the patient-derived variants in vitro and in vivo greatly furthers the understanding of the underlying pathomechanisms. New therapeutic options like AAV-mediated GRT in the context of kidney diseases are emerging and might pave the way for causal treatment approaches in SRNS.

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