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Background Variants in genes encoding nuclear pore complex (NPC) proteins are a newly identified cause of paediatric steroid-resistant nephrotic syndrome (SRNS). Recent reports describing  NUP93  variants suggest these could be a significant cause of paediatric onset SRNS. We report  NUP93  cases in the UK and demonstrate in vivo functional effects of  Nup93  depletion in a fly ( Drosophila melanogaster)  nephrocyte model. Methods Three hundred thirty-seven paediatric SRNS patients from the National cohort of patients with Nephrotic Syndrome (NephroS) were whole exome and/or whole genome sequenced. Patients were screened for over 70 genes known to be associated with Nephrotic Syndrome (NS).  D. melanogaster Nup93  knockdown was achieved by RNA interference using nephrocyte-restricted drivers. Results Six novel homozygous and compound heterozygous  NUP93  variants were detected in 3 sporadic and 2 familial paediatric onset SRNS characterised histologically by focal segmental glomerulosclerosis (FSGS) and progressing to kidney failure by 12 months from clinical diagnosis. Silencing of the two orthologs of human  NUP93  expressed in  D. melanogaster ,  Nup93-1 , and  Nup93-2  resulted in significant signal reduction of up to 82% in adult pericardial nephrocytes with concomitant disruption of NPC protein expression. Additionally, nephrocyte morphology was highly abnormal in  Nup93-1  and  Nup93-2  silenced flies surviving to adulthood. Conclusion We expand the spectrum of  NUP93  variants detected in paediatric onset SRNS and demonstrate its incidence within a national cohort. Silencing of either  D. melanogaster Nup93  ortholog caused a severe nephrocyte phenotype, signaling an important role for the nucleoporin complex in podocyte biology. Graphical Abstract A higher resolution version of the Graphical abstract is available as Supplementary information

Exploring the relevance of NUP93 variants in steroid-resistant nephrotic syndrome using next generation sequencing and a fly kidney model