Mutations in NUP160 Are Implicated in Steroid-Resistant Nephrotic Syndrome

Abstract

BackgroundStudies have identified mutations in >50 genes that can lead to monogenic steroid-resistant nephrotic syndrome (SRNS). The NUP160 gene, which encodes one of the protein components of the nuclear pore complex nucleoporin 160 kD (Nup160), is expressed in both human and mouse kidney cells. Knockdown of NUP160 impairs mouse podocytes in cell culture. Recently, siblings with SRNS and proteinuria in a nonconsanguineous family were found to carry compound-heterozygous mutations in NUP160.MethodsWe identified NUP160 mutations by whole-exome and Sanger sequencing of genomic DNA from a young girl with familial SRNS and FSGS who did not carry mutations in other genes known to be associated with SRNS. We performed in vivo functional validation studies on the NUP160 mutations using a Drosophila model.ResultsWe identified two compound-heterozygous NUP160 mutations, NUP160R1173× and NUP160E803K. We showed that silencing of Drosophila NUP160 specifically in nephrocytes (fly renal cells) led to functional abnormalities, reduced cell size and nuclear volume, and disorganized nuclear membrane structure. These defects were completely rescued by expression of the wild-type human NUP160 gene in nephrocytes. By contrast, expression of the NUP160 mutant allele NUP160R1173× completely failed to rescue nephrocyte phenotypes, and mutant allele NUP160E803K rescued only nuclear pore complex and nuclear lamin localization defects.ConclusionsMutations in NUP160 are implicated in SRNS. Our findings indicate that NUP160 should be included in the SRNS diagnostic gene panel to identify additional patients with SRNS and homozygous or compound-heterozygous NUP160 mutations and further strengthen the evidence that NUP160 mutations can cause SRNS.

Genetic Basis of Steroid Resistant Nephrotic Syndrome

“…Mutations in these nuclear pore complex protein genes lead to abnormal nucleoprotein assembly, thereby inhibiting podocyte proliferation, promoting podocyte apoptosis, and disrupting the structural integrity of the GFB. Mutations in these genes were mostly found to underlie childhoodonset AR-FSGS [27][28][29] .…”

The New Compound Heterozygous Mutation of NUP Nephropathy: Report of Two Cases and Literature Review

“…Apoptotic cells in the glomeruli and renal tubules cells were mentioned in some cases, which it might be the typical change of NUP nephropathy [1]. Small amount of immune complex deposition was observed in some cases but massive deposition of immune complex was reported in only one patient with IgA 4 + by immuno uorescence [19]. Two patients underwent repeated renal biopsy.…”

“…Two patients underwent repeated renal biopsy. One patient was found to have increased IgA deposition [19] and the other had pathological transformation from minimal change disease (MCD) to FSGS after 2 years [1], suggesting that performing renal biopsy at different time points may give different impressions of the pathological types. According to the limited reports, patients with NUP nephropathy were unresponsive to either steroids or immunosuppressants.…”

“…Since the discovery of the linkage between NUP107 gene mutation to SRNS syndrome in 2015, renal involvement resulting from NPCs mutation has been [9,19,20]). We studied the correlations between NUP gene mutations and clinical manifestations by reviewing the literatures published on PubMed Database (http://www.pubmed.com) up to January 2021.…”

Early-onset COQ8B (ADCK4) glomerulopathy in a child with isolated proteinuria: a case report and literature review

“…With the development of gene detection technology for pathogenic variants, genes that result in SRNS have attracted wide attention. Currently, at least 50 genes have been identified to lead to monogenic SRNS [ 19 , 20 ]. A Chinese study [ 7 ] presents the spectrum of mutations among the Chinese children with SRNS, in which the most common mutated gene is COQ8B ( ADCK4 ), followed by NPHS1 , WT1 , and NPHS2 .…”