Genetic diagnosis of steroid-resistant nephrotic syndrome in a longitudinal collection of Czech and Slovak patients: a high proportion of causative variants in NUP93

Bezdíčka, Martin; Stolbova, Sarka; Seeman, Tomáš; Cinek, Ondřej; Malina, Michal; Simánková, N; Průhová, Štěpánka; Zieg, Jakub

doi:10.1007/s00467-018-3950-2

Cited by 35 publications

(39 citation statements)

References 53 publications

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“…We identified novel compound heterozygous mutations of NUP93 gene using WES in a patient with nephrotic syndrome progressing to ESRD in the first decade of life. Fourteen patients were reported to have NUP93 mutations associated with SRNS [4–6]. Nup93 variants were first reported in 9 families with isolated SRNS [5].…”

Section: Discussionmentioning

confidence: 99%

“…Knockdown of NUP93 leads to inhibition of podocytes proliferation by impairing SMAD signaling resulting in focal segmental glomerulosclerosis (FSGS). Mutations of NUP93 have been shown to cause non-syndromic autosomal recessive FSGS, that can progress to ESRD within ten years [4, 5]. Here we describe a case of novel NUP93 mutations in a child with a syndromic SRNS phenotype.…”

Section: Introductionmentioning

confidence: 92%

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

Sandokji

Marquez

et al. 2019

BMC Nephrol

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Background Monogenic mutations may be a significant cause of steroid-resistant nephrotic syndrome. NUP93 is a gene previously reported to cause isolated steroid-resistant nephrotic syndrome. Case presentation Here we describe a case of recessive, syndromic, steroid-resistant nephrotic syndrome caused by NUP93 mutation. Conclusions NUP93 may convey a phenotype that has not only SRNS, but also other syndromic features.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 92%

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

Sandokji

Marquez

et al. 2019

BMC Nephrol

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“…Thus far, only two studies have reported mutations of NUP93 in SRNS 14,15 . Herein, we describe a NUP93 biallelic mutation in a 9-year-old boy with FSGS: one mutation was a novel heterozygous truncating variant, whereas the other was a heterozygous intronic variant, the pathogenicity of which was unknown.…”

Section: Introductionmentioning

confidence: 99%

Molecular assay for an intronic variant in NUP93 that causes steroid resistant nephrotic syndrome

et al. 2019

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Advances in molecular genetics have revealed that approximately 30% of cases with steroid resistant nephrotic syndrome (SRNS) are caused by single-gene mutations. More than genes are responsible for SRNS. One such gene is the nucleoporin, 93-KD (NUP93). Thus far, few studies have reported mutations of NUP93 in SRNS. Here, we describe an NUP93 biallelic mutation in a 9-year-old boy with focal segmental glomerular sclerosis (FSGS). Notably, one mutation comprised an intronic variant; we conducted in vivo and in vitro analysis to characterize this variant. We found two heterozygous mutations in NUP93: c.2137-18G>A in intron 19 and a novel nonsense mutation c.727A>T (p.Lys243*) in exon 8. We conducted RNA sequencing and in vitro splicing assays by using minigene construction, combined with protein expression analysis to determine the pathogenicity of the intronic variant. Both RNA sequencing and in vitro splicing assay showed exon 20 skipping by the intronic variant. In protein expression analysis, aberrant subcellular localization with small punctate vesicles in the cytoplasm was observed for the intronic variant. Taken together, we concluded that c.2137-18G>A was linked to pathogenicity due to aberrant splicing. NUP93 variants are quite rare; however, we have shown that even intronic variants in NUP93 can cause SRNS. This study provides a fundamental approach to validate the intronic variant, as well as new insights regarding the clinical spectrum of SRNS caused by rare gene variants.

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“…Lastly, in 2 additional patients with biopsy-proven FSGS, heterozygous missense variants in 2 known FSGS genes, CD2AP (P46) and ACTN4 (P43), were detected. However, because of the relative allele frequency in the general population (0.02% and 0.05%, respectively) and inconclusive in silico prediction, particularly in case of the recently reported ACTN4 variant (p.Ala427Thr), 24 both changes were classified as VUS (Supplementary Table S4). In P43, parental segregation showed paternal transmission in the absence of a significant renal phenotype in the father at 60 years of age.…”

Section: Resultsmentioning

confidence: 99%

Value of renal gene panel diagnostics in adults waiting for kidney transplantation due to undetermined end-stage renal disease

Ottlewski

Münch

Wagner³

et al. 2019

Kidney International

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End-stage renal disease (ESRD) of undetermined etiology is highly prevalent and constitutes a significant clinical challenge, particularly in the context of kidney transplantation (KT). Despite the identification of numerous rare hereditary nephropathies over the last few decades, patients with undetermined ESRD are not being systematically investigated for rare genetic causes in clinical practice. To address this, we utilized mutation analysis in patients on the kidney transplant waitlist and scrutinized underlying renal diagnoses of 142 patients in a single center KT-waitlist. This cohort was stratified into 85 cases of determined and 57 cases of undetermined ESRD. The latter patients were analyzed by a renal gene panel for mutations in 209 genes associated with ESRD. The most likely genetic diagnoses in 12% of the tested individuals with undetermined ESRD were established. All of these patients showed mutations in genes encoding components of the glomerular filtration barrier. Taken together, hereditary nephropathies, including autosomal dominant polycystic kidney disease, were identified in 35 of the 142 patients of the waitlist cohort. By significantly increasing the proportion of hereditary diagnoses from 29 to 35 patients, the rate of undetermined ESRD significantly decreased from 57 to 51 patients. This study demonstrates the beneficial use of genetic diagnostics in significantly unraveling undetermined ESRD cases prior to KT. Thus, in the absence of renal histology or the presence of unspecific histological conditions, such as hypertensive nephrosclerosis, focal segmental glomerulosclerosis or thrombotic microangiopathy, genetic analysis may provide a robust and specific renal diagnosis and allow for optimizing pre-and post-KT management.

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Genetic diagnosis of steroid-resistant nephrotic syndrome in a longitudinal collection of Czech and Slovak patients: a high proportion of causative variants in NUP93

Cited by 35 publications

References 53 publications

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

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

Molecular assay for an intronic variant in NUP93 that causes steroid resistant nephrotic syndrome

Value of renal gene panel diagnostics in adults waiting for kidney transplantation due to undetermined end-stage renal disease

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