NUP93 – familial idiopathic steroid-resistant nephrotic syndrome

NUP93, encoding nucleoporin 93, is a component of the nuclear pore complex. Biallelic variants in NUP93 underlie familial idiopathic steroid-resistant nephrotic syndrome and manifest as focal segmental glomerulosclerosis progressing to end-stage kidney disease.

In the first reported post-transplant recurrence of nephrotic syndrome, a 3-year-old boy carried compound heterozygous c.1772G>T (p.Gly591Val) and c.1916T>C (p.Leu639Pro) variants and developed ESKD by age 3; recurrent proteinuria after renal allograft required plasma exchange until remission was achieved with rituximab. Both parents were heterozygous asymptomatic carriers (PMID:30577294).

In a multi-patient cohort, one of four children with biallelic nucleoporin variants harbored NUP93 c.1235A>C (p.Asp412Ala), presented with steroid-resistant nephrotic syndrome at age 5 and progressed to ESKD (PMID:38650033).

Functional studies demonstrated that patient NUP93 p.Arg525Trp and p.Tyr629Cys variants resulted in markedly reduced nuclear immunofluorescence in glomerular and extraglomerular kidney cells (PMID:31517150), whereas the intronic c.2137-18G>A variant caused exon 20 skipping and cytoplasmic mislocalization in minigene assays, accompanied by a novel nonsense c.727A>T (p.Lys243Ter) variant disrupting NUP93 function (PMID:31015583).

Overall, NUP93-related steroid-resistant nephrotic syndrome follows autosomal recessive inheritance with a variant spectrum of missense (n = 5), nonsense (n = 1) and splice (n = 1) alleles, including a recurrent European founder c.1772G>T (p.Gly591Val).

Integrating genetic findings with functional concordance supports a loss-of-function mechanism. NUP93 testing is clinically informative for diagnosis, prognostication, and management of familial steroid-resistant nephrotic syndrome.

References

• Transplantation proceedings • 2018 • First Report of Recurrent Nephrotic Syndrome After Kidney Transplantation in a Patient With NUP93 Gene Mutations: A Case Report. PMID:30577294
• Unspecified Journal • 2023 • Title not provided. PMID:38650033
• Kidney international reports • 2019 • In Viv Expression of NUP93 and Its Alteration by NUP93 Mutations Causing Focal Segmental Glomerulosclerosis. PMID:31517150
• Journal of human genetics • 2019 • Molecular assay for an intronic variant in NUP93 that causes steroid resistant nephrotic syndrome. PMID:31015583

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