Exploring genotype-phenotype correlation in nucleoporin nephropathy

Nucleoporin nephropathy, a rare genetic kidney disorder, is not well-characterized despite its early onset in childhood.

We analyzed the clinical and genetic data of pediatric patients diagnosed with nucleoporin nephropathy at a southern Chinese pediatric nephrology center, and reviewed global cases reported up until July 2024.

In our center, five pediatric patients (aged 10 months to 8 years) were diagnosed with nucleoporin nephropathy. Three presented with steroid-resistant nephrotic syndrome, and one had initial extrarenal symptoms. All patients progressed to end-stage kidney disease. Global data shows 111 cases of nucleoporin nephropathy; 76.6% of patients initially presented with nephrotic syndrome, unresponsive to steroids or immunosuppressive therapy. 89.4% progressed to end-stage kidney disease in adolescence. Among the 37 transplant recipients, only 2 had proteinuria recurrence. Neurological symptoms were observed in a significant portion of patients, with variation across genotypes. East Asian patients, who account for 40.4% of the cases, often exhibit compound heterozygous missense, early renal involvement, and fewer extrarenal symptoms.

Routine nucleoporin gene testing is advised for Asian children with steroid-resistant nephrotic syndrome or end-stage kidney disease to prevent unnecessary treatments. While kidney transplantation has a favorable outlook, managing extrarenal symptoms of nucleoporin pehropathy is challenging.

Explore the link between nucleoporin gene mutations and disease phenotypes for a new understanding of NUP nephropathy. The renal phenotypes associated with NUP mutations display a remarkably consistent pattern as early-onset SRNS and progression to ESKD in adolescence. Highlight the importance in finding and managing the extrarenal symptoms associated with nucleoporin nephropathy. Regional specificities in NUP gene mutations are becoming apparent, with East Asian patients often presenting compound heterozygous mutations, early onset, rapid progression to end-stage kidney disease, and fewer extrarenal symptoms. Emphasize the necessity of nucleoporin gene testing for Asian children to prevent ineffective treatments.