NUP133 – Steroid-Resistant Nephrotic Syndrome

NUP133 has emerged as a critical gene whose disruption results in steroid‑resistant nephrotic syndrome (SRNS). Multiple studies have implicated nucleoporins in the assembly and stability of the nuclear pore complex, with NUP133 playing a central role in maintaining podocyte function. In cohorts comprising 13 families (PMID:30179222), pathogenic variants in NUP133 have been observed to segregate with SRNS, providing compelling genetic evidence for a disease association. This discovery underscores the contribution of nuclear pore dysfunction to the renal phenotype observed in affected individuals. The evidence spans both genetic and experimental approaches, reinforcing the gene–disease link. The integration of segregation data and functional analyses substantiates NUP133 as a disease‐relevant gene.

Detailed genetic studies have recorded several variants in NUP133 from unrelated families with SRNS. Among these, the variant c.2922T>G (p.Ser974Arg) has been identified in affected individuals, serving as a representative example of the deleterious alterations detected. This variant, along with others detected in similar genetic contexts, was consistently found in the evaluation of large multiplex families (PMID:30179222). Segregation analysis in these families confirms autosomal recessive transmission of the pathogenic alleles. The genetic evidence, therefore, fulfills critical criteria for a robust gene–disease association. Such findings provide clinicians with tangible targets for molecular diagnostic testing.

In addition to the genetic associations, functional investigations have advanced our understanding of the pathogenic mechanism. Experimental assessments using CRISPR/Cas9 knockout models in human podocytes have demonstrated that loss of NUP133 disrupts nuclear pore assembly, leads to misregulation of the podocyte transcriptome, and impairs cytoskeletal dynamics (PMID:35455939). These in vitro studies have recapitulated key aspects of the SRNS phenotype, lending biological plausibility to the observed genetic findings. Moreover, the functional assays have verified that the defects in nuclear pore complex formation directly impact the specialized functions of podocytes—cells essential for kidney filtration. The concordance between experimental data and clinical observations strengthens the case for NUP133’s involvement in SRNS.

Integrating both strands of evidence, the genetic data from multiple families and the functional studies converge to validate the association between NUP133 and SRNS. This integration supports a strong gene–disease association, with experimental data complementing the molecular genetic findings. Although additional evidence exists beyond the current scoring ceiling, the collected data provide a comprehensive foundation for diagnostic decision‑making. The consistent pattern of inheritance and reproducible experimental outcomes firmly establish the pathogenic role of NUP133 mutations in SRNS.

Key Take‑home: The demonstrated association between NUP133 and steroid‑resistant nephrotic syndrome offers significant clinical utility for diagnostics and therapeutic development, reinforcing the role of nuclear pore integrity in podocyte health.

References

• The Journal of Clinical Investigation • 2018 • Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome PMID:30179222
• Cells • 2022 • NUP133 Controls Nuclear Pore Assembly, Transcriptome Composition, and Cytoskeleton Regulation in Podocytes PMID:35455939

Evidence Based Scoring (AI generated)