scholarly journals Polypoid Change of the Glomerular Basement Membrane in a Child with Steroid Resistant Nephrotic Syndrome and ARHGAP24 Mutation: A Case Report

2016 ◽  
Vol 9 (1) ◽  
pp. 88-93 ◽  
Author(s):  
Anna Francis ◽  
John Burke ◽  
Leo Francis ◽  
Steven McTaggart ◽  
Andrew Mallett
Keyword(s):  
Nephrotic Syndrome ◽  
Basement Membrane ◽  
Gene Product ◽  
Glomerular Basement Membrane ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
Membrane Ruffling ◽  
Genes Encoding ◽  
Important Player

Background: Steroid resistant nephrotic syndrome (SRNS) is increasingly recognised to have a genetic basis following the identification of a number of mutations within genes encoding podocyte and basement membrane proteins. The ARHGAP24 gene product is a recently recognised important player in podocyte interaction with the glomerular basement membrane. The ARHGAP24 gene encodes a protein involved in regulating cell motility, membrane structure and polarity. Mutations in the gene have been shown in vitro to cause cell membrane ruffling. Case Presentation: We report a novel missense mutation in exon 4 (c.[284G>A]; p.[Arg95Gln]) of the ARHGAP24 gene in a child that presented with SRNS at four years of age. Renal biopsy demonstrated unusual polypoid changes of the glomerular basement membrane (GBM). Conclusion: We propose this novel ARHGAP24 mutation as causative for SRNS associated with unusual polypoid basement membrane changes. These biopsy findings, in association with ARHGAP24 mutation and clinical nephrotic syndrome are a novel finding. This finding may advance the understanding of ARHGAP24 gene product function.

scholarly journals P1802EVALUATION OF THE GENETICAL FEATURES AFFECTING THE RENAL OUTCOMES IN CHILDREN WITH STEROID RESISTANT NEPHROTIC SYNDROME

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Elif Comak ◽  
Aslı Toylu ◽  
Ugur Bilge ◽  
Gülsah Kaya Aksoy ◽  
Mustafa Koyun ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Target Genes ◽  
Immunosuppressive Agents ◽  
Gene Panel ◽  
Sequencing Analysis ◽  
Single Nucleotide Variants ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
Genes Encoding ◽  
Renal Prognosis

Abstract Background and Aims Nephrotic syndrome in childhood is characterized by proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Although most children respond to glucocorticoid therapy, approximately 10% of patients turn out to be steroid resistant (steroid-resistant nephrotic syndrome [SRNS]). Although several studies in children with SRNS have shown that mutations in genes encoding proteins in the podocyte skeleton may be responsible for the etiology in only one-third of cases, the genetic features related with renal prognosis and response to immunosuppressive agents are not fully recognized. The aim of this study was to investigate the genomic alterations associated with renal prognosis and resistance to immunosuppression in children with SRNS. Method The children with SRNS were enrolled in this study. Custom gene panel was designed for next-generation sequencing analysis of more than 20 target genes (ABCB1, ABCC2, CTLA4, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, FOXP3, GSTP1, IMPDH1, IMPDH2, NOS3, NR3C1, SLCO1B1, SLCO1B3, TPMT, UGT1A9, UGT2B7) and 200 single nucleotide variants (SNVs) which were reported as implicated in renal prognosis of nephrotic syndrome. The target gene panel was enriched for drug metabolism regulating transporters and enzymes. Results A total of 25 children, 16 boys (64%), median age at last visit 17.5 years (13-18 years), median age at diagnosis 7.5 years (2-15), median follow-up 9.58±4.54 years, were included in the study. All patients were diagnosed focal segmental glomerulosclerosis on renal biopsy.

scholarly journals ADCK4 Deficiency Destabilizes the Coenzyme Q Complex, Which Is Rescued by 2,4-Dihydroxybenzoic Acid Treatment

2020 ◽  
Vol 31 (6) ◽  
pp. 1191-1211 ◽  
Author(s):  
Eugen Widmeier ◽  
Seyoung Yu ◽  
Anish Nag ◽  
Youn Wook Chung ◽  
Makiko Nakayama ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Knockout Mice ◽  
Molecular Mechanisms ◽  
Coenzyme Q ◽  
Mass Spectrometry Analysis ◽  
Dihydroxybenzoic Acid ◽  
Mitochondrial Potential ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome

BackgroundMutations in ADCK4 (aarF domain containing kinase 4) generally manifest as steroid-resistant nephrotic syndrome and induce coenzyme Q10 (CoQ10) deficiency. However, the molecular mechanisms underlying steroid-resistant nephrotic syndrome resulting from ADCK4 mutations are not well understood, largely because the function of ADCK4 remains unknown.MethodsTo elucidate the ADCK4’s function in podocytes, we generated a podocyte-specific, Adck4-knockout mouse model and a human podocyte cell line featuring knockout of ADCK4. These knockout mice and podocytes were then treated with 2,4-dihydroxybenzoic acid (2,4-diHB), a CoQ10 precursor analogue, or with a vehicle only. We also performed proteomic mass spectrometry analysis to further elucidate ADCK4’s function.ResultsAbsence of Adck4 in mouse podocytes caused FSGS and albuminuria, recapitulating features of nephrotic syndrome caused by ADCK4 mutations. In vitro studies revealed that ADCK4-knockout podocytes had significantly reduced CoQ10 concentration, respiratory chain activity, and mitochondrial potential, and subsequently displayed an increase in the number of dysmorphic mitochondria. However, treatment of 3-month-old knockout mice or ADCK4-knockout cells with 2,4-diHB prevented the development of renal dysfunction and reversed mitochondrial dysfunction in podocytes. Moreover, ADCK4 interacted with mitochondrial proteins such as COQ5, as well as cytoplasmic proteins such as myosin and heat shock proteins. Thus, ADCK4 knockout decreased the COQ complex level, but overexpression of ADCK4 in ADCK4-knockout podocytes transfected with wild-type ADCK4 rescued the COQ5 level.ConclusionsOur study shows that ADCK4 is required for CoQ10 biosynthesis and mitochondrial function in podocytes, and suggests that ADCK4 in podocytes stabilizes proteins in complex Q in podocytes. Our study also suggests a potential treatment strategy for nephrotic syndrome resulting from ADCK4 mutations.

Steroid-resistant nephrotic syndrome in children: A mini-review on genetic mechanisms, predictive biomarkers and pharmacotherapy strategies

2020 ◽  
Vol 26 ◽  
Author(s):  
Hong-Li Guo ◽  
Ling Li ◽  
Ze-Yue Xu ◽  
Xia Jing ◽  
Ying Xia ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Molecular Mechanisms ◽  
Single Gene ◽  
Predictive Biomarkers ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
Genes Encoding ◽  
Standardized Treatment ◽  
Associated Proteins ◽  
Genetic Mechanisms

: Steroid-resistant nephrotic syndrome (SRNS) constitutes the second most frequent cause of chronic kidney disease in childhood. The etiology of SRNS remains largely unknown and no standardized treatment exists. Recent advances in genomics have helped to build understanding about the molecular mechanisms and pathogenesis of the disease. The genetic polymorphisms in genes encoding proteins which are involved in the pharmacokinetics and pharmacodynamics of glucocorticoids (GCs) partially account for the different responses between patients with nephrotic syndrome. More importantly, single-gene causation in podocytes-associated proteins were found in approximately 30% of SRNS patients. Some potential biomarkers have been tested for their abilities to discriminate against pediatric patients who are sensitive to GCs treatment and patients who are resistant to the same therapy. This article reviews the recent findings on genetic mechanisms, predictive biomarkers and current therapies for SRNS with the goal to improve the management of children with this syndrome.

scholarly journals TBC1D8B Mutations Implicate RAB11-Dependent Vesicular Trafficking in the Pathogenesis of Nephrotic Syndrome

2019 ◽  
Vol 30 (12) ◽  
pp. 2338-2353 ◽  
Author(s):  
Lina L. Kampf ◽  
Ronen Schneider ◽  
Lea Gerstner ◽  
Roland Thünauer ◽  
Mengmeng Chen ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Slit Diaphragm ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Cellular Functions ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
Whole Exome ◽  
Immortalized Cell

BackgroundMutations in about 50 genes have been identified as monogenic causes of nephrotic syndrome, a frequent cause of CKD. These genes delineated the pathogenetic pathways and rendered significant insight into podocyte biology.MethodsWe used whole-exome sequencing to identify novel monogenic causes of steroid-resistant nephrotic syndrome (SRNS). We analyzed the functional significance of an SRNS-associated gene in vitro and in podocyte-like Drosophila nephrocytes.ResultsWe identified hemizygous missense mutations in the gene TBC1D8B in five families with nephrotic syndrome. Coimmunoprecipitation assays indicated interactions between TBC1D8B and active forms of RAB11. Silencing TBC1D8B in HEK293T cells increased basal autophagy and exocytosis, two cellular functions that are independently regulated by RAB11. This suggests that TBC1D8B plays a regulatory role by inhibiting endogenous RAB11. Coimmunoprecipitation assays showed TBC1D8B also interacts with the slit diaphragm protein nephrin, and colocalizes with it in immortalized cell lines. Overexpressed murine Tbc1d8b with patient-derived mutations had lower affinity for endogenous RAB11 and nephrin compared with wild-type Tbc1d8b protein. Knockdown of Tbc1d8b in Drosophila impaired function of the podocyte-like nephrocytes, and caused mistrafficking of Sns, the Drosophila ortholog of nephrin. Expression of Rab11 RNAi in nephrocytes entailed defective delivery of slit diaphragm protein to the membrane, whereas RAB11 overexpression revealed a partial phenotypic overlap to Tbc1d8b loss of function.ConclusionsNovel mutations in TBC1D8B are monogenic causes of SRNS. This gene inhibits RAB11. Our findings suggest that RAB11-dependent vesicular nephrin trafficking plays a role in the pathogenesis of nephrotic syndrome.

scholarly journals Steroid-resistant nephrotic syndrome associated MYO1E mutations have differential effects on myosin 1e localization, dynamics, and activity

2021 ◽  
Author(s):  
Pei-Ju Liu ◽  
Laura K Gunther ◽  
Diana Perez ◽  
Jing Bi-Karchin ◽  
Christopher D Pellenz ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Protein Sequence ◽  
Expression System ◽  
Cell Junctions ◽  
Wild Type ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
Adenoviral Infection

Myo1e is a non-muscle motor protein enriched in the podocyte foot processes. Mutations in MYO1E are associated with steroid-resistant nephrotic syndrome (SRNS). Here, we set out to differentiate between the pathogenic and neutral MYO1E variants identified in SRNS patients by exome sequencing. Based on protein sequence conservation and structural predictions, two mutations in the motor domain, T119I and D388H, were selected for this study. EGFP-tagged Myo1e constructs were delivered into the Myo1e-KO podocytes via adenoviral infection to analyze Myo1e protein stability, Myo1e localization, and clathrin-dependent endocytosis, which is known to involve Myo1e activity. Furthermore, truncated Myo1e constructs were expressed using the baculoviral expression system and used to measure Myo1e ATPase and motor activity in vitro. Both mutants were expressed as full-length proteins in the Myo1e-KO podocytes. However, unlike wild-type (WT) Myo1e, the T119I variant was not enriched at the cell junctions or clathrin-coated vesicles (CCVs) in podocytes. In contrast, the D388H variant localization was similar to the WT. Surprisingly, the dissociation of the D388H variant from cell-cell junctions and CCVs was decreased, suggesting that this mutation also affects Myo1e activity. The ATPase activity and the ability to translocate actin filaments were drastically reduced for the D388H mutant, supporting the findings from cell-based experiments. The experimental pipeline developed in this study allowed us to determine that the T119I and D388H mutations appear to be pathogenic and gain additional knowledge in the Myo1e role in podocytes. This workflow can be applied to the future characterization of novel MYO1E variants associated with SRNS.

scholarly journals GAPVD1 and ANKFY1 Mutations Implicate RAB5 Regulation in Nephrotic Syndrome

2018 ◽  
Vol 29 (8) ◽  
pp. 2123-2138 ◽  
Author(s):  
Tobias Hermle ◽  
Ronen Schneider ◽  
David Schapiro ◽  
Daniela A. Braun ◽  
Amelie T. van der Ven ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Binding Affinity ◽  
Ectopic Expression ◽  
Physical Interaction ◽  
Missense Mutations ◽  
Wild Type ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
Whole Exome

BackgroundSteroid-resistant nephrotic syndrome (SRNS) is a frequent cause of CKD. The discovery of monogenic causes of SRNS has revealed specific pathogenetic pathways, but these monogenic causes do not explain all cases of SRNS.MethodsTo identify novel monogenic causes of SRNS, we screened 665 patients by whole-exome sequencing. We then evaluated the in vitro functional significance of two genes and the mutations therein that we discovered through this sequencing and conducted complementary studies in podocyte-like Drosophila nephrocytes.ResultsWe identified conserved, homozygous missense mutations of GAPVD1 in two families with early-onset NS and a homozygous missense mutation of ANKFY1 in two siblings with SRNS. GAPVD1 and ANKFY1 interact with the endosomal regulator RAB5. Coimmunoprecipitation assays indicated interaction between GAPVD1 and ANKFY1 proteins, which also colocalized when expressed in HEK293T cells. Silencing either protein diminished the podocyte migration rate. Compared with wild-type GAPVD1 and ANKFY1, the mutated proteins produced upon ectopic expression of GAPVD1 or ANKFY1 bearing the patient-derived mutations exhibited altered binding affinity for active RAB5 and reduced ability to rescue the knockout-induced defect in podocyte migration. Coimmunoprecipitation assays further demonstrated a physical interaction between nephrin and GAPVD1, and immunofluorescence revealed partial colocalization of these proteins in rat glomeruli. The patient-derived GAPVD1 mutations reduced nephrin-GAPVD1 binding affinity. In Drosophila, silencing Gapvd1 impaired endocytosis and caused mistrafficking of the nephrin ortholog.ConclusionsMutations in GAPVD1 and probably in ANKFY1 are novel monogenic causes of NS. The discovery of these genes implicates RAB5 regulation in the pathogenesis of human NS.

A rare cause of steroid-resistant nephrotic syndrome in a child: Answers

2019 ◽  
Vol 35 (4) ◽  
pp. 621-623
Author(s):  
Lale Guliyeva ◽  
Yılmaz Tabel ◽  
Ali Düzova ◽  
Nusret Akpolat ◽  
Seza Özen ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome

Whole-Exome Sequencing Solved over 2-Decade Kidney Disease Enigma

Nephron ◽  
2021 ◽  
pp. 1-6
Author(s):  
Suramath Isaranuwatchai ◽  
Ankanee Chanakul ◽  
Chupong Ittiwut ◽  
Chalurmpon Srichomthong ◽  
Vorasuk Shotelersuk ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Kidney Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Treatment Plan ◽  
Unknown Etiology ◽  
Pediatric Case ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
Whole Exome

Chronic kidney disease of unknown etiology (CKDu) has been a problem in renal practice as indefinite diagnosis may lead to inappropriate management. Here, we report a 54-year-old father diagnosed with CKDu at 33 years old and his 8-year-old son with steroid-resistant nephrotic syndrome. Using whole-exome sequencing, both were found to be heterozygous for c.737G>A (p.Arg246Gln) in LMX1B. The diagnosis of LMX1B-associated nephropathy has led to changes in the treatment plan with appropriate genetic counseling. The previously reported cases with this particular mutation were also reviewed. Most children with LMX1B-associated nephropathy had nonnephrotic proteinuria with normal renal function. Interestingly, our pediatric case presented with steroid-resistant nephrotic syndrome at 8 years old and progressed to ESRD requiring peritoneal dialysis at the age of 15 years. Our report emphasized the need of genetic testing in CKDu for definite diagnosis leading to precise management.

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