Collapsing Focal Segmental Glomerulosclerosis in Siblings With Compound Heterozygous Variants in NUP93 Expand the Spectrum of Kidney Phenotypes Associated With Nucleoporin Gene Mutations

Abstract

BackgroundFocal segmental glomerulosclerosis (FSGS) is a major cause of end stage kidney disease, with the collapsing form having the worst prognosis. Study of families with hereditary FSGS has provided insight into disease mechanisms.MethodsIn this report, we describe a sibling pair with NUP93 mutations and collapsing FSGS (cFSGS). For each brother, we performed next generation sequencing and segregation analysis by direct sequencing. To determine if the variants found in the index family are a common cause of cFSGS, we screened 7 patients with cFSGS, gleaned from our cohort of 200 patients with FSGS, for variants in NUP93 as well as for APOL1 high-risk genotypes.ResultsWe identified segregating compound heterozygous NUP93 variants (1) c.1772G > T p.G591V, 2) c.2084T > C p.L695S) in the two brothers. We did not find any pathogenic variants in the seven patients with cFSGS from our cohort, and as expected five of these seven patients carried the APOL1 high-risk genotype.ConclusionTo the best of our knowledge, this is the first report of cFSGS in patients with NUP93 mutations, based on this report, mutations in NUP93 and other nucleoporin genes should be considered when evaluating a child with familial cFSGS. Determining the mechanisms by which these variants cause cFSGS may provide insight into the pathogenesis of the more common primary and virus-mediated forms of cFSGS.

Cytokine storm–based mechanisms for extrapulmonary manifestations of SARS-CoV-2 infection

“…These data suggest that the Zhx2 hypomorph state is associated with an early and rapid transit of pSTAT5 and pSTAT6 from cytosol into the nucleus, and also with reduced generation of pSTAT6 upon cytokine cocktail activation. Future studies will explore the potential effects of transcriptional factor ZHX2 on nuclear pore protein gene expression, since mutations in one of these genes has been noted in a family with FSGS collapsing variant (48).…”

“…All animals received humane treatment per protocol. Methods for dynabead assisted mouse glomerular isolation, rat glomerular isolation by sieving, histological section tissue preservation, timed 18-hour urine collection in metabolic cages in the absence of food, assessment of albuminuria and proteinuria, real time PCR, confocal imaging, electron microscopy and sample processing, histology for light microscopy, Western blot, coimmunoprecipitation and APOL1 genotyping are previously described (27,40,41,48,(56)(57)(58).…”

Collapsing glomerulopathy: unraveling varied pathogeneses

“…Mandibuloacral dysplasia type B is a rare autosomal recessive disorder caused by mutations in zinc metalloproteinase ZMPSTE24, which manifests with defects in prelaminin A processing and collapsing glomerulopathy [45]. Patients with mutations in TRPC6, an ACTN4 phosphorylation site and, most recently, NUP93 have also presented with nephrotic syndrome and renal biopsies demonstrating collapsing glomerulopathy [46][47][48]. The mechanisms underlying collapsing glomerulopathy in these rare genetic diseases are largely speculative at this stage, although all three of these genes have been linked to nephrotic syndrome and FSGS, only a fraction of the reported variants are reported with collapsing glomerulopathy.…”

From the sideline: Tissue‐specific nucleoporin function in health and disease, an update

“…Since the first report by Braun et al, numerous mutations in NUP93 (Fig. 3, Table 1) have been identified in patients with SRNS or focal segmental glomeruloscelerosis (FSGS; MIM 603278), a precursor state of SRNS [73][74][75][76][77][78][79][80][81][82]). In SRNS, podocytes, specialised epithelial cells that line the nephrons of the kidney, are mainly affected.…”