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Background: Genetic nephrotic syndrome is caused by pathogenic variants in genes encoding proteins necessary for the stability and functionality of the glomerular filtration barrier. To date, more than 70 genes associated with steroid-resistant nephrotic syndrome have been identified. Summary: We review the clinical and molecular aspects of genetic nephrotic syndrome with a particular focus on genes associated with slit membrane and podocyte cytoskeleton defects. Sanger sequencing and next-generation sequencing are widely used in the identification of novel gene variants and help us gain a better understanding of the disease. Despite these findings, therapy is mainly supportive and focused on the reduction of proteinuria and management of chronic kidney disease with an unfavorable outcome for a significant proportion of cases. Positive therapeutic effects of immunosuppressive drugs have been reported in some patients; however, their long-time administration cannot be generally recommended. Conclusion: Personalized treatment based on understanding the distinct disease pathogenesis is needed. With this, it will be possible to avoid harmful immunosuppressive therapy and improve outcomes and quality of life for pediatric patients suffering from genetic nephrotic syndrome. [ABSTRACT FROM AUTHOR]

Approximately one third of children with steroid-resistant nephrotic syndrome (SRNS) carry pathogenic variants in one of the many associated genes. The WT1 gene coding for the WT1 transcription factor is among the most frequently affected genes. Cases from the Czech national SRNS database were sequenced for exons 8 and 9 of the WT1 gene. Eight distinct exonic WT1 variants in nine children were found. Three children presented with isolated SRNS, while the other six manifested with additional features. To analyze the impact of WT1 genetic variants, wild type and mutant WT1 proteins were prepared and the DNA-binding affinity of these proteins to the target EGR1 sequence was measured by microscale thermophoresis. Three WT1 mutants showed significantly decreased DNA-binding affinity (p.Arg439Pro, p.His450Arg and p.Arg463Ter), another three mutants showed significantly increased binding affinity (p.Gln447Pro, p.Asp469Asn and p.His474Arg), and the two remaining mutants (p.Cys433Tyr and p.Arg467Trp) showed no change of DNA-binding affinity. The protein products of WT1 pathogenic variants had variable DNA-binding affinity, and no clear correlation with the clinical symptoms of the patients. Further research is needed to clarify the mechanisms of action of the distinct WT1 mutants; this could potentially lead to individualized treatment of a so far unfavourable disease. [ABSTRACT FROM AUTHOR]