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NPHS2 Revisited Through 208 Cases and Podocin Complex Modeling
Nils David Mertens1, Camille Nicolas Frank1, Leah Bolsius1
1Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Kidney International Reports
|April 6, 2026
Summary
Steroid-resistant nephrotic syndrome (SRNS) is linked to NPHS2 gene variants. This study reveals genotype-phenotype correlations and proposes podocin
Area of Science:
- Genetics
- Molecular Biology
- Nephrology
Background:
- Steroid-resistant nephrotic syndrome (SRNS) is a major cause of chronic kidney disease in young individuals.
- Biallelic variants in the NPHS2 gene, encoding podocin, are the most frequent monogenic cause of SRNS.
- Understanding NPHS2 genotype-phenotype relationships and podocin's structure is crucial for diagnosis and treatment.
Purpose of the Study:
- To investigate genotype-phenotype correlations in a large cohort of patients with NPHS2 variants.
- To elucidate the higher-order assembly architecture of podocin using advanced structural modeling.
- To improve the assessment of NPHS2 variants of unknown significance.
Main Methods:
- Analysis of clinical data from 208 individuals with pathogenic NPHS2 variants.
- Application of in silico pathogenicity prediction tools (REVEL, EVE) and evolutionary modeling.
- High-order structural modeling using AlphaFold3 to predict podocin assembly architecture.
Main Results:
- Identified a wide spectrum of NPHS2 allelic variants and variable disease onset.
- Correlated specific genotypes (e.g., p.R229Q, p.V180M) with later disease onset.
- Proposed a novel AI-generated model of podocin higher-order assemblies with variants clustering at oligomer interfaces.
Conclusions:
- Delineated genotype-phenotype relationships for NPHS2-associated SRNS.
- Proposed a structural model for podocin assemblies, aiding variant assessment.
- Highlighted the need for experimental validation of structural findings.
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