Identification of novel mutations and phenotype in the steroid resistant nephrotic syndrome gene NUP93: a case report

Sandokji, Ibrahim; Marquez, Jonathan; Ji, Weizhen; Zerillo, Cynthia; Konstantino, Monica; Lakhani, Saquib A.; Khokha, Mustafa K.

doi:10.1186/s12882-019-1458-z

Cited by 9 publications

(16 citation statements)

References 12 publications

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“…Phenotypes are listed in Table 2 and compare with previously-reported cases [10,11,[21][22][23][24]. All had multi-drug resistant focal segmental glomerulosclerosis (FSGS), progressing rapidly to CKD stage 5 within 2-12 months and required kidney transplant.…”

Section: Resultsmentioning

confidence: 99%

“…Sandokji et al recently reported a 5-year-old girl presenting with SRNS, cardiomyopathy and developmental delay with autistic features. After kidney transplant, she had self-limiting proteinuria which resolved within a week [24] Nucleoporins are known to have a role in the immune system. Although there is no corresponding NUP93 mouse model, NUP210 knockout mice develop peripheral T-cell alterations [44] while NUP96 + / − animals present selective alterations of the immune system [45].…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in 7 nuclear pore associated genes, NUP85, NUP107, NUP133, NUP160, NUP205, XP05 and NUP93 have recently been implicated in paediatric SRNS forming the first kidney-specific example of NPC dysfunction [11,19,20]. To date, 15 different NUP93 mutations are reported in 16 SRNS patients with the most common variant, p.(Gly591Val), found in 9/16 cases [11,[21][22][23][24]. We recently described a UK cohort of paediatric SRNS patients, collected via a national UK Renal Registry (RaDaR) [25].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…This is in contrast with the common observation of less likelihood of disease recurrence post‐transplant in vast majority of patients with SRNS due to inherited gene mutations 1 . Sandokji et al reported a 5‐year‐old non‐consanguineous female of African American and Hispanic origin with NUP93 variant resulting in ESRD and renal transplant with no recurrence 9 …”

Section: Discussionmentioning

confidence: 79%

“… 1 Sandokji et al reported a 5‐year‐old non‐consanguineous female of African American and Hispanic origin with NUP93 variant resulting in ESRD and renal transplant with no recurrence. 9 We identified a homozygous NUP93 novel sequence variant in a consanguineous Indian girl who had a rapidly progressive ESRD in the first decade of life with no disease recurrence in the post‐transplant period.…”

Section: Discussionmentioning

confidence: 98%

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

Acharya

Upadhyay

2021

Clinical Case Reports

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

Jühlen,

Fahrenkrog

2023

FEBS Letters

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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.

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Identification of novel mutations and phenotype in the steroid resistant nephrotic syndrome gene NUP93: a case report

Cited by 9 publications

References 12 publications

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

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

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

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

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