Nephrotic Syndrome, Type 17

A number sign (#) is used with this entry because of evidence that nephrotic syndrome type 17 (NPHS17) is caused by homozygous or compound heterozygous mutation in the NUP85 gene (170285) on chromosome 17q25.

For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome, see NPHS1 (256300).

Clinical Features

Braun et al. (2018) reported 4 patients from 3 unrelated families who presented between 4 and 11 years of age with steroid-resistant nephrotic syndrome and microscopic hematuria. Renal biopsy showed focal segmental glomerulosclerosis. Three patients progressed to end-stage renal disease between 7 and 12 years of age. Two unrelated patients had short stature, and 2 sibs in 1 family had intellectual disability.

Inheritance

The transmission pattern of NPHS17 in the families reported by Braun et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 patients from 3 unrelated families with NPHS17, Braun et al. (2018) identified homozygous or compound heterozygous mutations in the NUP85 gene (170285.0001-170285.0004). The mutations were found by high-throughput targeted exon sequencing and were demonstrated to segregate in the 2 families from whom parental DNA was available for study. In vitro functional expression studies showed that most of the mutations weakened the interaction of NUP85 with NUP160 (607614) and were unable to fully rescue abnormal kidney morphology in nup85-null Xenopus embryos, consistent with a loss of function. CRISPR/Cas9-mediated knockout of NUP85 in human podocytes increased the formation of filopodia and was associated with increased CDC42 (116952) activity, suggesting alteration of actin and cytoskeletal dynamics. CRISPR/Cas9-mediated knockout of the nup85 gene in zebrafish embryos resulted in developmental abnormalities, including small eyes, body axis curvature, and edema, as well as early lethality. The patients were part of a large study in which various nucleopore (NUP) genes were found to be mutated in NPHS, suggesting a common pathogenic pathway.

Animal Model

Braun et al. (2018) found that morpholino knockdown of nup85 in Xenopus embryos resulted in abnormal pronephros morphology, consistent with a defect in glomerulogenesis. Expression of human wildtype NUP85 rescued the defect. CRISPR/Cas9-mediated knockout of the nup85 gene in zebrafish embryos resulted in developmental abnormalities, including small eyes, body axis curvature, and edema, as well as early lethality.