Core Components of the Nuclear Pore Bind Distinct States of Chromatin and Contribute to Polycomb Repression.

Interactions between the genome and the nuclear pore complex (NPC) have been implicated in multiple gene regulatory processes, but the underlying logic of these interactions remains poorly defined. Here, we report high-resolution chromatin binding maps of two core components of the NPC, Nup107 and Nup93, in Drosophila cells. Our investigation uncovered differential binding of these NPC subunits, where Nup107 preferentially targets active genes while Nup93 associates primarily with Polycomb-silenced regions. Comparison to Lamin-associated domains (LADs) revealed that NPC binding sites can be found within LADs, demonstrating a linear binding of the genome along the nuclear envelope. Importantly, we identified a functional role of Nup93 in silencing of Polycomb target genes and in spatial folding of Polycomb domains. Our findings lend to a model where different nuclear pores bind different types of chromatin via interactions with specific NPC sub-complexes, and a subset of Polycomb domains is stabilized by interactions with Nup93.

SUN5, a testis-specific nuclear membrane protein, participates in recruitment and export of nuclear mRNA in spermatogenesis.

SUN5, a testis-specific gene, is associated with acephalic spermatozoa syndrome (ASS). Here, we demonstrate that Sun5 is involved in mRNA export. In Sun5-knockout mice ( Sun5 -/-), poly(A) + RNA accumulates in the nuclei of germ cells, leading to reduced sperm counts, decreased sperm motility and disrupted sperm head-to-tail junctions. Additionally, in the GC-2 germ cell line with RNA interference of Sun5, heterogeneous nuclear ribonucleoproteins (hnRNPs) and poly (A) + RNA (mainly mRNA) are retained in the nucleus. Further mechanistic studies reveal that Sun5 interacts with Nxf1 (nuclear RNA export factor 1) and nucleoporin 93 (Nup93). Interference with Nup93 inhibits mRNA export. Treatment with leptomycin B to block the CRM1 pathway indicates that Sun5 regulates mRNA export through an Nxf1-dependent pathway. In Sun5 -/- mice, the binding of Nxf1 and Nup93 decreases due to loss of Sun5 function, and the process of submitting Nxf1-binding mRNPs to Nup93 is inhibited, resulting in abnormal spermatogenesis. Together, these data may elucidate a novel pathway for mRNA export in male germ cells.

Nup93 and CTCF modulate spatiotemporal dynamics and function of the HOXA gene locus during differentiation.

Nucleoporins regulate nuclear transport and are also involved in DNA damage, repair, cell cycle, chromatin organization and gene expression. Here, we studied the role of nucleoporin Nup93 and the chromatin organizer CTCF in regulating expression of the HOXA gene locus during differentiation. ChIP sequencing revealed a significant overlap between Nup93 and CTCF peaks. Interestingly, Nup93 and CTCF are associated with the 3' and 5' HOXA genes, respectively. Depletions of Nup93 and CTCF antagonistically modulate expression levels of 3' and 5' HOXA genes in the undifferentiated human NT2/D1 cell line. Nup93 also regulates the localization of the HOXA gene locus, which disengages from the nuclear periphery upon Nup93 but not CTCF depletion, consistent with its upregulation. The dynamic association of Nup93 and CTCF with the HOXA locus during differentiation correlates with its spatial positioning and expression. Whereas Nup93 tethers the HOXA locus to the nuclear periphery, CTCF potentially regulates looping of the HOXA gene cluster in a temporal manner. In summary, Nup93 and CTCF complement one another in modulating the spatiotemporal dynamics and function of the HOXA gene locus during differentiation. This article has an associated First Person interview with the first authors of the paper.

Downregulation of NUP93 aggravates hypoxia-induced death of cardiomyocytes in vitro through abnormal regulation of gene transcription.

Nuclear pore complex in the nuclear envelope plays an important role in controlling the transportation of RNAs, proteins and other macromolecules between the nucleus and cytoplasm. The relationship between abnormal expression of nucleoporins and cardiovascular diseases is unclear. In this study we investigated how myocardial infarction affected the expression and function of nucleoporins in cardiomyocytes. We separately knocked down 27 nucleoporins in rat primary myocardial cells. Among 27 nucleoporins, knockdown of Nup93, Nup210 and Nup214 markedly increased the expression of ANP and BNP, two molecular markers of cardiomyocyte function. We showed that Nup93 was significantly downregulated in hypoxic cardiomyocytes. Knockdown of Nup93 aggravated hypoxia-induced injury and cell death of cardiomyocytes, whereas overexpression of Nup93 led to the opposite effects. RNA-seq and bioinformatics analysis revealed that knockdown of Nup93 did not affect the overall transportation of mRNAs from the nucleus to the cytoplasm, but regulated the transcription of a large number of mRNAs in cardiomyocytes, which are mainly involved in oxidative phosphorylation and ribosome subunits. Most of the down-regulated genes by Nup93 knockdown overlapped with the genes whose promoters could be directly bound by Nup93. Among these genes, we demonstrated that Nup93 knockdown significantly down-regulated the expression of YAP1. Overexpression of YAP1 partially rescued the function of Nup93 knockdown and attenuated the effects of hypoxia on cell injury and cardiomyocyte death. We conclude that down-regulation of Nup93, at least partially, contributes to hypoxia-induced injury and cardiomyocyte death through abnormal interaction with the genome to dynamically regulate the transcription of YAP1 and other genes. These results reveal a new mechanism of Nup93 and might provide new therapeutic targets for the treatment of ischemia-induced heart failure.

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

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. A higher resolution version of the Graphical abstract is available as Supplementary information.

A self-inhibitory interaction within Nup155 and membrane binding are required for nuclear pore complex formation.

Nuclear pore complexes (NPCs) are gateways through the nuclear envelope. How they form into a structure containing three rings and integrate into the nuclear envelope remains a challenging paradigm for coordinated assembly of macro-complexes. In vertebrates, the cytoplasmic and nucleoplasmic rings of NPCs are mostly formed by multiple copies of the Nup107-Nup160 complex, whereas the central, or inner ring is composed of Nup53, Nup93, Nup155 and the two paralogues Nup188 and Nup205. Inner ring assembly is only partially understood. Using in vitro nuclear assembly reactions, we show that direct pore membrane binding of Nup155 is crucial for NPC formation. Replacing full-length Nup155 with its N-terminal ß-propeller allows assembly of the outer ring components to the NPC backbone that also contains Nup53. However, further assembly, especially recruitment of the Nup93 and Nup62 complexes, is blocked. Self-interaction between the N- and C-terminal domains of Nup155 has an auto-inhibitory function that prevents interaction between the N-terminus of Nup155 and the C-terminal region of Nup53. Nup93 can overcome this block by binding to Nup53, thereby promoting formation of the inner ring and the NPC.

SARS coronavirus protein nsp1 disrupts localization of Nup93 from the nuclear pore complex.

Severe acute respiratory syndrome coronavirus nonstructural protein 1 (nsp1) is a key factor in virus-induced down-regulation of host gene expression. In infected cells, nsp1 engages in a multipronged mechanism to inhibit host gene expression by binding to the 40S ribosome to block the assembly of translationally competent ribosome, and then inducing endonucleolytic cleavage and the degradation of host mRNAs. Here, we report a previously undetected mechanism by which nsp1 exploits the nuclear pore complex and disrupts the nuclear-cytoplasmic transport of biomolecules. We identified members of the nuclear pore complex from the nsp1-associated protein assembly and found that the expression of nsp1 in HEK cells disrupts Nup93 localization around the nuclear envelope without triggering proteolytic degradation, while the nuclear lamina remains unperturbed. Consistent with its role in host shutoff, nsp1 alters the nuclear-cytoplasmic distribution of an RNA binding protein, nucleolin. Our results suggest that nsp1, alone, can regulate multiple steps of gene expression including nuclear-cytoplasmic transport.

Visceral leishmaniasis: A novel nuclear envelope protein 'nucleoporins-93 (NUP-93)' from Leishmania donovani prompts macrophage signaling for T-cell activation towards host protective immune response.

The shift of macrophage and T-cell repertoires towards proinflammatory cytokine signalling ensures the generation of host-protective machinery that is otherwise compromised in cases of the intracellular Leishmania parasite. Different groups have attempted to restore host protective immunity. These vaccine candidates showed good responses and protective effects in murine models, but they generally failed during human trials. In the present study, we evaluated the effect of 97 kDa recombinant nucleoporin-93 of Leishmania donovani (rLd-NUP93) on mononuclear cells in healthy and treated visceral leishmaniasis (VL) patients and on THP-1 cell lines. rLd-NUP93 stimulation increased the expression of the early lymphocyte activation marker CD69 on CD4+ and CD8+ T cells. The expression of the host protective pro-inflammatory cytokines IFN-γ, IL-12 and TNF-α was increased, with a corresponding down-regulation of IL-10 and TGF-ß upon rLd-NUP93 stimulation. This immune polarization resulted in the up-regulation of NF-κB p50 with scant expression of SMAD-4. Augmenting lymphocyte proliferation upon priming with rLd-NUP93 ensured its potential for activation and generation of strong T-cell mediated immune responses. This stimulation extended the leishmanicidal activity of macrophages by releasing high amounts of reactive oxygen species (ROS). Further, the leishmanicidal activity of macrophages was intensified by the elevated production of nitric oxide (NO). The fact that this antigen was earlier reported in circulating immune complexes of VL patients highlights its antigenic importance. In addition, in silico analysis suggested the presence of MHC class I and II-restricted epitopes that proficiently trigger CD8+ and CD4+ T-cells, respectively. This study reported that rLd-NUP93 was an effective immunoprophylactic agent that can be explored in future vaccine design.

Biallelic Variants in the Nuclear Pore Complex Protein NUP93 Are Associated with Non-progressive Congenital Ataxia.

Nuclear pore complexes (NPCs) are the gateways of the nuclear envelope mediating transport between cytoplasm and nucleus. They form huge complexes of 125 MDa in vertebrates and consist of about 30 different nucleoporins present in multiple copies in each complex. Here, we describe pathogenic variants in the nucleoporin 93 (NUP93) associated with an autosomal recessive form of congenital ataxia. Two rare compound heterozygous variants of NUP93 were identified by whole exome sequencing in two brothers with isolated cerebellar atrophy: one missense variant (p.R537W) results in a protein which does not localize to NPCs and cannot functionally replace the wild type protein, whereas the variant (p.F699L) apparently supports NPC assembly. In addition to its recently described pathological role in steroid-resistant nephrotic syndrome, our work identifies NUP93 as a candidate gene for non-progressive congenital ataxia.

Expression of Nup93 is associated with the proliferation, migration and invasion capacity of cervical cancer cells.

Cervical cancer is a prevalent and devastating malignancy in females worldwide. Nucleoporin 93 (Nup93), a member of the nuclear pore complex, plays an important role in transport across the nuclear pore. Several nucleoporins have been linked to cancer. However, the oncogenic role and underlying mechanism of Nup93 in cervical cancer development have not been reported. In this study, the expression of Nup93 was analyzed by quantitative real-time polymerase chain reaction (qPCR), western blot analysis, and immunohistochemical staining in cervical cancer tissues and cell lines. We found that the expression of Nup93 was higher in cervical cancer samples, compared to normal cervical samples. The knockdown of Nup93 inhibited cell proliferation, migration, and invasion capacity of cervical cancer cells. At the same time, we also found that silencing of Nup93 could inhibit cellular migration and invasion by regulating cytoskeleton actin and Rho family proteins. Nup93 also participated in the IL-6/STAT3 signaling pathway. In addition, down-regulation of Nup93 prevented tumor formation in mice in vivo. Thus, Nup93 may be a carcinogenic gene and serve as a potential therapeutic target for cervical cancer.

Nucleoporin 93, a new substrate of the E3 ubiquitin protein ligase HECTD1, promotes esophageal squamous cell carcinoma progression.

Nucleoporin 93 (NUP93) is an important component of the nuclear pore complex, exhibiting pro-tumorigenic properties in some cancers. However, its function in esophageal squamous cell carcinoma (ESCC) has not been elucidated. This study aimed to investigate the effects of NUP93 in ESCC and the underlying mechanisms involved. Through analysis of public human cancer datasets, we observed higher expression of NUP93 in esophageal cancer tissues than in normal tissues. Stable ESCC cell lines with NUP93 overexpression or knockdown were established by lentiviral vector transduction and puromycin selection. NUP93 knockdown suppressed the proliferation, colony formation, cell cycle transition, migration, and invasion of ESCC cells, while the overexpression of NUP93 displayed opposite effects. NUP93 positively regulated epithelial-mesenchymal transition and AKT signaling transduction in ESCC cells. In addition, NUP93 increased the expression of programmed death ligand 1 (PD-L1) in ESCC cells and attenuated NK cell-mediated lysis of ESCC cells. In vivo experiments demonstrated that NUP93 promotes the growth of ESCC in nude mice, enhances Ki67 and PD-L1 expression, and promotes AKT signaling transduction in xenografts. Mechanistically, we demonstrated that the HECT domain E3 ubiquitin protein ligase 1 (HECTD1) contributes to the ubiquitination and degradation of NUP93 and acts as a tumor suppressor in ESCC. To conclude, this study has shown that NUP93 has pro-tumor properties in ESCC and that HECTD1 functions as an upstream regulator of NUP93 in ESCC. These findings may contribute to the investigation of potential therapeutic targets in ESCC.

Transcription Factor yin-Yang 1 augments nucleoporin 93 oncogene activity and modulates bladder Cancer malignancy.

OBJECTIVE: This study aims to investigate the functional interplay between transcription factor YY1 and nucleoporin 93 (NUP93) in regulating the malignancy of bladder cancer cells. METHODS: NUP93 expressions in bladder cancer tissues and normal counterparts were analyzed using a public dataset and clinical samples. NUP93 and Yin Yang 1 (YY1) mRNA expression and protein levels in T24 and RT4 cells were determined by Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. The effect of NUP93 knockdown on the proliferation, migration, and invasion capabilities of cells was evaluated. Concurrently, transcriptional regulation of NUP93 by YY1 was confirmed using a dual luciferase assay. The effect of NUP93 knockdown on tumorigenesis was evaluate in a subcutaneous xenograft mouse model. RESULTS: Elevated levels of NUP93 in bladder cancer tissues and cell lines were observed. Silencing NUP93 significantly suppressed glycolysis, impeded the growth, migration, invasion and tumor formation of bladder cancer cells. The transcription factor YY1 acted as a positive regulator to upregulate NUP93 expression. YY1 overexpression partially rescued the effects of NUP93 silencing on bladder cancer cells. CONCLUSION: Our results uncovered transcription factor YY1 as a positive regulator of NUP93 expression, and NUP93 serves as an oncogenic factor to sustain the malignancy of bladder cancer cells. These findings suggest that targeting the YY1-NUP93 axis could offer novel therapeutic strategies for bladder cancer treatment.

Mutations in the NUP93, NUP107 and NUP160 genes cause steroid-resistant nephrotic syndrome in Chinese children.

BACKGROUND: The variants of nucleoporins are extremely rare in hereditary steroid-resistant nephrotic syndrome (SRNS). Most of the patients carrying such variants progress to end stage kidney disease (ESKD) in their childhood. More clinical and genetic data from these patients are needed to characterize their genotype-phenotype relationships and elucidate the role of nucleoporins in SRNS. METHODS: Four patients of SRNS carrying biallelic variants in the NUP93, NUP107 and NUP160 genes were presented. The clinical and molecular genetic characteristics of these patients were summarized, and relevant literature was reviewed. RESULTS: All four patients in this study were female and initially presented with SRNS. The median age at the onset of the disease was 5.08 years, ranging from 1 to 10.5 years. Among the four patients, three progressed to ESKD at a median age of 7 years, ranging from 1.5 to 10.5 years, while one patient reached stage 3 chronic kidney disease (CKD3). Kidney biopsies revealed focal segmental glomerulosclerosis in three patients. Biallelic variants were detected in NUP93 in one patient, NUP107 in two patients, as well as NUP160 in one patient respectively. Among these variants, five yielded single amino acid substitutions, one led to nonsense mutation causing premature termination of NUP107 translation, one caused a single nucleotide deletion resulting in frameshift and truncation of NUP107. Furthermore, one splicing donor mutation was observed in NUP160. None of these variants had been reported previously. CONCLUSION: This report indicates that biallelic variants in NUP93, NUP107 and NUP160 can cause severe early-onset SRNS, which rapidly progresses to ESKD. Moreover, these findings expand the spectrum of phenotypes and genotypes and highlight the importance of next-generation sequencing in elucidating the molecular basis of SRNS and allowing rational treatment for affected individuals.

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

The subcellular compartmentalisation of eukaryotic cells requires selective exchange between the cytoplasm and the nucleus. Intact nucleocytoplasmic transport is vital for normal cell function and mutations in the executing machinery have been causally linked to human disease. Central players in nucleocytoplasmic exchange are nuclear pore complexes (NPCs), which are built from ~30 distinct proteins collectively termed nucleoporins. Aberrant nucleoporin expression was detected in human cancers and autoimmune diseases since quite some time, while it was through the increasing use of next generation sequencing that mutations in nucleoporin genes associated with mainly rare hereditary diseases were revealed. The number of newly identified mutations is steadily increasing, as is the number of diseases. Mutational hotspots have emerged: mutations in the scaffold nucleoporins seemingly affect primarily inner organs, such as heart, kidney, and ovaries, whereas genetic alterations in peripheral, cytoplasmic nucleoporins affect primarily the central nervous system and development. In this review, we summarise latest insights on altered nucleoporin function in the context of human hereditary disorders, with a focus on those where mechanistic insights are beginning to emerge.

Steroid-Resistant Nephrotic Syndrome Caused by NUP93 Pathogenic Variants.

BACKGROUND: Although steroid therapy is a standard of care for nephrotic syndrome treatment, 15-20% of patients do not respond to it. Finding the genetic background is possible in >10% of steroid-resistant nephrotic syndrome (SRNS) cases. Variants in genes encoding nuclear pore complex proteins are a novel cause of paediatric steroid-resistant nephrotic syndrome (SRNS). Recent studies suggest NUP93 variants to be a significant cause of paediatric onset SRNS. The clinical data on certain variants and disease history are still very limited. METHODS AND RESULTS: We report the SRNS case of a 12-year-old boy with two detected NUP93 variants, which are pathogenic and possibly pathogenic. The onset of the disease was early and severe. The patient was admitted to the paediatric nephrology department due to nephrotic-range proteinuria and hypoalbuminemia with a long medical history of steroid and non-steroid immunosuppressive treatment. The genetic panel targeting 50 genes, clinically relevant for nephrotic syndrome, was performed. The only gene which was found to be affected by mutations, namely c.2326C>T and c.1162C>T, respectively, was NUP93. Conclusions: NUP93 variants are rarely identified as causes of SRNS. Clinical data are of utmost importance to establish the standard of care for SRNS patients suffering from this genetic disfunction. This is the first case of a heterozygous patient with the c.2326C>T and c.1162C>T variants and confirmed clinical history of the SRNS described so far. Our data suggest the clinical relevance of the c.1162C>T variant.

Nucleoporin 93 mediates ß-catenin nuclear import to promote hepatocellular carcinoma progression and metastasis.

Nuclear pore complex (NPC) embedded in the nuclear envelope, is the only channel for macromolecule nucleocytoplasmic transportation and has important biological functions. However, the deregulation of specific nucleoporins (Nups) and NPC-Nup-based mechanisms and their function in tumour progression remain poorly understood. Here, we aimed to identify the Nups that contribute to HCC progression and metastasis in 729 primary hepatocellular carcinoma (HCC) cases using molecular, cytological, and biochemical techniques. Our results revealed elevated Nup93 expression in HCC tissues, especially in cases with metastasis, and was linked to worse prognosis. Furthermore, Nup93 knockdown suppressed HCC cell metastasis and proliferation, while Nup93 overexpression promoted these activities. We observed that Nup93 promotes HCC metastasis and proliferation by regulating ß-catenin translocation. In addition, we found that Nup93 interacted with ß-catenin directly, independent of importin. Furthermore, LEF1 and ß-catenin facilitated the Nup93-mediated metastasis and proliferation in HCC via a positive feedback loop. Thus, our findings provide novel insights into the mechanisms underlying the Nup93-induced promotion of HCC metastasis and suggest potential therapeutic targets in the LEF1-Nup93-ß-catenin pathway for HCC therapeutics.

End-stage renal disease in a child with focal segmental glomerulosclerosis associated with a homozygous NUP93 variant.

This report highlights that the genetic causes of FSGS, including NUP93 gene variant, such as the one described in this report, progress to end-stage renal disease rapidly and that the risk of recurrence post-renal transplantation is less likely.

Molecular and structural analysis of central transport channel in complex with Nup93 of nuclear pore complex.

The central transport channel (CTC) of nuclear pore complexes (NPCs) is made up of three nucleoporins Nup62, Nup58 and Nup54. In which manner and capacity, these nucleoporins form the CTC, is not yet clear. We explored the CTC Nups from various species and observed that distinct biochemical characteristics of CTC Nups are evolutionarily conserved. Moreover, comparative biochemical analysis of CTC complexes showed various stoichiometric combinations of Nup62, Nup54 and Nup58 coexisting together. We observed the conserved amino-terminal domain of mammalian Nup93 is crucial for the anchorage of CTC and its localization to NPCs. We could reconstitute and purify mammalian CTC·Nup93 quaternary complex by co-expressing full length or N-terminal domain of Nup93 along with CTC complex. Further, we characterized CTC·Nup93 complex using small angle X-ray scattering and electron microscopy that revealed a "V" shape of CTC·Nup93 complex. Overall, this study demonstrated for the first time evolutionarily conserved plasticity and stoichiometric diversity in CTC Nups.

In Vivo Expression of NUP93 and Its Alteration by NUP93 Mutations Causing Focal Segmental Glomerulosclerosis.

INTRODUCTION: Mutations in genes encoding nucleoporins (NUPs; components of nuclear pore complexes [NPCs]), such as NUP93, have been reported to cause steroid-resistant nephrotic syndrome (SRNS) or focal segmental glomerulosclerosis (FSGS), which often progresses to end-stage renal disease (ESRD) in childhood. The expression of NUP93 in renal or extrarenal tissues, and the mechanism by which NUP93 mutations cause this renal phenotype, remain unclear. METHODS: The expression of NUP93 in normal control kidney and in a patient with FSGS carrying NUP93 mutations was examined by immunofluorescence analysis. The expression of NUP93 in blood cells was analyzed by Western blot analysis. RESULTS: Immunofluorescence analysis detected NUP93 expression in nuclei of all glomerular and tubulointerstitial cells in human kidneys. Whole-exome sequencing identified a compound heterozygous NUP93 mutation comprising a novel missense mutation p.Arg525Trp, and a previously reported mutation, p.Tyr629Cys, in a patient with FSGS that developed ESRD at the age of 6 years. In the patient's kidney, the intensity of NUP93 immunofluorescence was significantly decreased in the nuclei of both glomerular and extraglomerular cells. The expression of CD2-associated protein (CD2AP) and nephrin in the patient's podocytes was relatively intact. The amount of NUP93 protein was not significantly altered in the peripheral blood mononuclear cells of the patient. CONCLUSION: NUP93 is expressed in the nuclei of all the cell types of the human kidney. Altered NUP93 expression in glomerular cells as well as extraglomerular cells by NUP93 mutations may underlie the pathogenic mechanism of SRNS or FSGS.