scholarly journals Mutations in KIRREL1, a slit diaphragm component, cause steroid-resistant nephrotic syndrome

2019 ◽  
Vol 96 (4) ◽  
pp. 883-889 ◽  
Author(s):  
Ashish K. Solanki ◽  
Eugen Widmeier ◽  
Ehtesham Arif ◽  
Shailza Sharma ◽  
Ankana Daga ◽  
...  
2019 ◽  
Vol 30 (12) ◽  
pp. 2338-2353 ◽  
Author(s):  
Lina L. Kampf ◽  
Ronen Schneider ◽  
Lea Gerstner ◽  
Roland Thünauer ◽  
Mengmeng Chen ◽  
...  

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.


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

Nephron ◽  
2021 ◽  
pp. 1-6
Author(s):  
Suramath Isaranuwatchai ◽  
Ankanee Chanakul ◽  
Chupong Ittiwut ◽  
Chalurmpon Srichomthong ◽  
Vorasuk Shotelersuk ◽  
...  

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.


2016 ◽  
Vol 31 (suppl_1) ◽  
pp. i353-i353
Author(s):  
Beata S. Lipska-Ziętkiewicz ◽  
Olivia Boyer ◽  
Olivier Gribouval ◽  
Mansoureh Tabatabaei ◽  
Cecile Fourrage ◽  
...  

2017 ◽  
Vol 32 (suppl_3) ◽  
pp. iii110-iii113
Author(s):  
Maddalena Gigante ◽  
Sterpeta Diella ◽  
Luisa Santangelo ◽  
Ottavio Amatruda ◽  
Gianluca Caridi ◽  
...  

2021 ◽  
pp. 13-17
Author(s):  
А.Е. Турсын

Описан клинический случай пациент с нефротическим синдромом, стероид резистентный вариант, с артериальной гипертензией, осложненный полисерозитом (гидроторакс, асцит, плеврит). Пациент поступил в клинику в состоянии средней степени тяжести, с массивными отеками, полисерозитом, артериальной гипертензией и выраженным нефротическим синдромом. Диагноз: Гломерулярная болезнь. Нефротический синдром, стероид резистентный вариант. Функция почек снижена (СКФ- 84мл/мин по Шварцу). Двухсторонний экссудативный плеврит. Гидроторакс. Полисерозит (в рамках нефротического синдрома) был установлен на основании выраженного нефротического синдрома. Пациенту была проведена патогенетическая терапия. Отмечено улучшение состояния больного, в виде снижения отеков, нормализаций артериального давления, что в свою очередь поспособствовало сохранению и улучшению качества жизни пациента. A clinical case of a patient with nephrotic syndrome, steroidresistant variant, with arterial hypertension complicated by polyserositis (hydrothorax, ascites, pleurisy) is described. The patient was admitted to the clinic in a state of moderate severity, with massive edema, polyserositis, arterial hypertension, and severe nephrotic syndrome. Diagnosis: Glomerular disease. Nephrotic syndrome, steroidresistant variant. The kidney function is reduced (GFR - 84 ml/min according to Schwartz). Bilateral exudative pleurisy. Hydrothorax. Polyserositis (within the framework of nephrotic syndrome) was established based on the severe nephrotic syndrome. The patient underwent pathogenetic therapy. An improvement in the patient's condition was noted, in the form of a decrease in edema, normalization of blood pressure, which in turn contributed to the preservation and improvement of the patient's quality of life.


2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Larisa Prikhodina ◽  
Svetlana Papizh ◽  
Inna Povolotskaya

Abstract Background and Aims Monogenic causes of steroid-resistant nephrotic syndrome (SRNS) have been reported for up to one-third of children depending on age of the disease onset. Immunosuppressive treatment of genetic SRNS with calcineurin inhibitors (CNIs) is still controversial. The aim of the study was to investigate the efficacy of CNIs with focus on inducing remission and long-term kidney function in children with monogenic SRNS. Method Retrospective analysis of efficacy CNIs in five children (2M/3F) with monogenic SRNS was performed. Kidney biopsy prior CNIs revealed FSGS (n=4) and MCD (n=1). The initial cyclosporine (CsA) dose was 5 mg/kg/24h to keep a target level of 80-150 ng/ml and tacrolimus (TAC) - 0.1 mg/kg/24h to achieve a target level of 5-10 ng/ml. CsA took all 5 patients with subsequent switching to TAC in 2 children due to cosmetic side effects. The median follow-up period was 165.0 (IQR: 59.0; 185.5) months. Next generation sequencing (NGS) was used for identification of pathogenic variants in all patients. Results The median age at onset of monogenic SRNS was 33.0 (IQR: 16.5; 63.0) months. 2/5 (40%) patients presented with acute SRNS, 1/5 (20%) child with infantile NS, 1/5 (20%) - with isolated nephrotic range proteinuria with hypoalbuminemia and 1/5 (20%) - with NS and extrarenal features of Nail-Patella syndrome. NGS identified previously described pathogenic variants in all 5 children, including NPHS2 homozygous c.28dup (p.Glu87Ter) (n=1), NPHS2 compound heterozygous c.868G>A (p.Val290Met) in combination with c.686G>A (p.Arg229Gln) (n=1), LMX1B heterozygous c.788T>G (p.Val263Gly) (n=1), LMX1B heterozygous c.737G>A (p.Arg246Gln) (n=1), and COL4A3 heterozygous c.2962G>A (p.Gly988Arg) variant (n=1). The median time from diagnosis to initiation of CNIs treatment was 72.0 (IQR: 33.0; 93.0) months. CNIs induced complete remission in 2/5 (40%) patients, presented with acute SRNS, including one girl with MCD due to NPHS2 compound heterozygous variants with mutation-dependent pathogenicity of one (p.R229Q) of them and one boy with FSGS due to COL4A3 heterozygous variant (n=1). Partial remission was induced by CNIs in 2/5 (40%) girls with FSGS due to LMX1B heterozygous variants with isolated SRNS (n=1) and Nail-Patella syndrome (n=1). The median duration of CNIs treatment to obtain complete or partial remission was 13.5 (IQR: 6.8; 15.8) months. Acute CNIs-associated nephrotoxicity had 2 patients with LMX1B variants. At the last follow up full and partial responders to CNIs treatment aged of 16.5 (IQR: 11.8; 17.5) years had CKD-1 (n=3) and CKD-2 (n=1). 1/5 (20%) boy with NPHS2-associated infantile NS was CNI resistant and developed CKD-5 at the age of 6.5 years with subsequent living related kidney transplantation. Conclusion We found that 4/5 (80%) children with monogenic SRNS demonstrated partial or full response to CNIs treatment with stable long-term kidney function. We assume that CNIs might improve podocyte function by stabilization of their cytoskeleton disrupted in patients with monogenic SRNS.


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