scholarly journals CUBN Gene Mutations May Cause Focal Segmental Glomerulosclerosis (FSGS) in Children

2021 ◽  
Author(s):  
Jing Yang ◽  
Yongli Xu ◽  
Linxia Deng ◽  
Luowen Zhou ◽  
Liru Qiu ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Mesangial Cells ◽  
Interstitial Fibrosis ◽  
Megaloblastic Anemia ◽  
Gene Mutations ◽  
Glomerular Sclerosis ◽  
Glomerular Mesangial Cells ◽  
Site Mutation ◽  
Genetic Characteristics ◽  
Intron Splice

Abstract Background: CUBN gene mutation is extremely rare and thought to only presented as tubular proteinuria without glomerular involvement. Here, we present 3 patients with prominent proteinuria and FSGS in renal pathologies caused by novel CUBN gene mutations.Method: Whole exome sequencing was performed in three children. CUBN gene mutations were found and then verified by sanger sequencing. Their clinical, pathological and molecular genetic characteristics were analyzed and correlated accordingly. Results: All three children presented with prominent proteinuria but normal or slightly higher levels of urine β2 microglobulin, without megaloblastic anemia. Renal biopsies showed segmental glomerular sclerosis, glomerular mesangial cells proliferation, effacement of foot processes, podocyte microvillation and interstitial fibrosis. There were four novel CUBN gene mutations in our study, including c.9287T>C (p.L3096P), c.122+1G>A, c.7906C>T (p.R2636*), c.10233G>A (p.W3411*). Except for intron splice-site mutation, all other variants are located in highly conserved sites of CUB domain. Conclusion: In this study, four novel pathogenic mutations of CUBN gene were identified in three prominent proteinuric children. The results demonstrate that CUBN gene mutations may cause pathological changes of podocytes and FSGS, which was not previously reported. Our cases extend the spectrum of renal manifestation and genotype of CUBN gene mutation.

scholarly journals CUBN gene mutations may cause focal segmental glomerulosclerosis (FSGS) in children

2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Jing Yang ◽  
Yongli Xu ◽  
Linxia Deng ◽  
Luowen Zhou ◽  
Liru Qiu ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Megaloblastic Anemia ◽  
Gene Mutations ◽  
Compound Heterozygous ◽  
Homozygous Mutation ◽  
Genetic Characteristics ◽  
Intron Splice ◽  
Pathogenic Variants ◽  
Segmental Glomerulosclerosis ◽  
Isolated Proteinuria

Abstract Background Imerslund-Gräsbeck Syndrome (IGS) is mainly caused by CUBN gene biallelic mutations. Proteinuria accompanies IGS specific symptoms in about half of the patients, isolated proteinuria is rarely reported. Here we present 3 patients with isolated proteinuria and focal segmental glomerulosclerosis (FSGS) caused by CUBN gene biallelic pathogenic variants. Method Whole exome sequencing was performed on three children with isolated proteinuria. CUBN gene biallelic pathogenic variants were found and then verified by sanger sequencing. Their clinical, pathological and molecular genetic characteristics were analyzed and correlated accordingly. Results All three children presented with isolated proteinuria, no megaloblastic anemia. Their urine levels of β2 microglobulin were normal or slightly higher. Renal biopsies showed focal segmental glomerulosclerosis with mild glomerular mesangial hypercellularity, partial effacement of foot processes and podocyte microvillation. Two of them were found to carry compound heterozygous mutations and one homozygous mutation of CUBN gene. Totally four CUBN gene biallelic pathogenic variants were identified, including c.9287 T > C (p.L3096P), c.122 + 1G > A, c.7906C > T (p.R2636*), c.10233G > A (p.W3411*). Except for intron splice-site mutation, all other variants are located in highly conserved sites of CUB domain for binding to albumin. Conclusion The results demonstrate that CUBN gene mutations may cause isolated proteinuria pathologically presented as FSGS. Our cases extend the spectrum of renal manifestation and genotype of CUBN gene mutations.

Colchicine attenuates renal injury in a model of hypertensive chronic kidney disease

2013 ◽  
Vol 305 (10) ◽  
pp. F1466-F1476 ◽  
Author(s):  
Tianxiu Guan ◽  
Bo Gao ◽  
Guang Chen ◽  
Xing Chen ◽  
Melissa Janssen ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Mechanical Strain ◽  
Tissue Growth ◽  
Glomerular Sclerosis ◽  
Glomerular Mesangial Cells ◽  
Rhoa Activation ◽  
Microtubule Disruption

Hypertension is a risk factor for chronic kidney disease, particularly when associated with impaired renal autoregulation and thereby increased intraglomerular pressure (Pgc). Elevated Pgc can be modeled in vitro by exposing glomerular mesangial cells to mechanical strain. We previously showed that RhoA mediates strain-induced matrix production. Here, we show that RhoA activation is dependent on an intact microtubule network. Upregulation of the profibrotic cytokine connective tissue growth factor (CTGF) by mechanical strain is dependent on RhoA activation and inhibited by microtubule disruption. We tested the effects of the microtubule depolymerizing agent colchicine in 5/6 nephrectomized rats, a model of chronic kidney disease driven by elevated Pgc. Colchicine inhibited glomerular RhoA activation and attenuated both glomerular sclerosis and interstitial fibrosis without affecting systemic blood pressure. Upregulation of the matrix proteins collagen I and fibronectin, as well as CTGF, was attenuated by colchicine. Activity of the profibrotic cytokine TGF-β, as assessed by Smad3 phosphorylation, was also inhibited by colchicine. Microtubule disruption significantly decreased renal infiltration of lymphocytes and macrophages. Our studies thus indicate that colchicine modifies hypertensive renal fibrosis. Its protective effects are likely mediated by inhibition of RhoA signaling and renal infiltration of inflammatory cells. Already well-established in clinical practice for other indications, prevention of hypertension-associated renal fibrosis may represent a new potential use for colchicine.

Platelet-activating factor and the kidney

1986 ◽  
Vol 251 (1) ◽  
pp. F1-F11 ◽  
Author(s):  
D. Schlondorff ◽  
R. Neuwirth
Keyword(s):  
De Novo ◽  
Mesangial Cells ◽  
Biological Activities ◽  
Platelet Activating Factor ◽  
Calcium Ionophore ◽  
Initial Step ◽  
Renal Physiology ◽  
Dependent Manner ◽  
Glomerular Mesangial Cells ◽  
Isolated Kidney

Platelet-activating factor (PAF) represents a group of phospholipids with the basic structure of 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine. A number of different cells are capable of producing PAF in response to various stimuli. The initial step of PAF formation is activation of phospholipase A2 in a calcium-dependent manner, yielding lyso-PAF. During this step arachidonic acid is also released and can be converted to its respective cyclooxygenase and lipoxygenase products. The lyso-PAF generated is then acetylated in position 2 of the glycerol backbone by a coenzyme A (CoA)-dependent acetyltransferase. An additional pathway may exist whereby PAF is generated de novo from 1-alkyl-2-acetyl-sn-glycerol by phosphocholine transferase. PAF inactivation in cells and blood is by specific acetylhydrolases. PAF exhibits a variety of biological activities including platelet and leukocyte aggregation and activation, increased vascular permeability, respiratory distress, decreased cardiac output, and hypotension. In the kidney PAF can produce decreases in blood flow, glomerular filtration, and fluid and electrolyte excretion. Intrarenal artery injection of PAF may also result in glomerular accumulation of platelets and leukocytes and mild proteinuria. PAF increases prostaglandin formation in the isolated kidney and in cultured glomerular mesangial cells. PAF also causes contraction of mesangial cells. Upon stimulation with calcium ionophore the isolated kidney, isolated glomeruli and medullary cells, and cultured mesangial cells are capable of producing PAF. The potential role for PAF in renal physiology and pathophysiology requires further investigation that may be complicated by 1) the multiple interactions of PAF, prostaglandins, and leukotrienes and 2) the autocoid nature of PAF, which may restrict its action to its site of generation.

scholarly journals Protective Effects of Ethanolic Extract from Rhizome of Polygoni avicularis against Renal Fibrosis and Inflammation in a Diabetic Nephropathy Model

2021 ◽  
Vol 22 (13) ◽  
pp. 7230
Author(s):  
Jung-Joo Yoon ◽  
Ji-Hun Park ◽  
Yun-Jung Lee ◽  
Hye-Yoom Kim ◽  
Byung-Hyuk Han ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Diabetic Nephropathy ◽  
Renal Dysfunction ◽  
Renal Fibrosis ◽  
Mesangial Cells ◽  
Resistance Index ◽  
Ethanolic Extract ◽  
Glomerular Sclerosis ◽  
Oral Glucose ◽  
Inflammatory Factor

Progressive diabetic nephropathy (DN) in diabetes leads to major morbidity and mortality. The major pathological alterations of DN include mesangial expansion, extracellular matrix alterations, tubulointerstitial fibrosis, and glomerular sclerosis. Polygoni avicularis is widely used in traditional oriental medicine and has long been used as a diuretic, astringent, insecticide and antihypertensive. However, to the best of the authors’ knowledge, the effects of the ethanolic extract from rhizome of Polygoni avicularis (ER-PA) on DN have not yet been assessed. The present study aimed to identify the effect of ER-PA on renal dysfunction, which has been implicated in DN in human renal mesangial cells and db/db mice and investigate its mechanism of action. The in vivo experiment was performed using Polygoni avicularis-ethanol soluble fraction (ER-PA) and was administrated to db/db mice at 10 and 50 mg/kg dose. For the in vitro experiments, the human renal mesangial cells were induced by high glucose (HG, 25 mM). The ER-PA group showed significant amelioration in oral glucose tolerance, and insulin resistance index. ER-PA significantly improved the albumin excretion and markedly reduced plasma creatinine, kidney injury molecule-1 and C-reactive protein. In addition, ER-PA significantly suppressed inflammatory cytokines. Histopathologically, ER-PA attenuated glomerular expansion and tubular fibrosis in db/db mice. Furthermore, ER-PA suppressed the expression of renal fibrosis biomarkers (TGF and Collagen IV). ER-PA also reduced the NLR family pyrin domain containing 3 inflammatory factor level. These results suggest that ER-PA has a protective effect against renal dysfunction through improved insulin resistance as well as the inhibition of nephritis and fibrosis in DN.

4-Jahres-Update der Murano-Studie bestätigt den Stellenwert von Venetoclax in der 2. Therapielinie der CLL

2021 ◽  
pp. 77-79
Author(s):  
Maximilian Schmutz ◽  
Sebastian Sommer
Keyword(s):  
Response Rate ◽  
Residual Disease ◽  
Gene Mutations ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Fixed Duration ◽  
Genetic Characteristics ◽  
Genomic Complexity ◽  
End Of Treatment

<b>Purpose:</b> In previous analyses of the MURANO study, fixed-duration venetoclax plus rituximab (VenR) resulted in improved progression-free survival (PFS) compared with bendamustine plus rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). At the 4-year follow-up, we report long-term outcomes, response to subsequent therapies, and the predictive value of molecular and genetic characteristics. <b>Patients and methods:</b> Patients with CLL were randomly assigned to 2 years of venetoclax (VenR for the first six cycles) or six cycles of BR. PFS, overall survival (OS), peripheral-blood minimal residual disease (MRD) status, genomic complexity (GC), and gene mutations were assessed. <b>Results:</b> Of 389 patients, 194 were assigned to VenR and 195 to BR. Four-year PFS and OS rates were higher with VenR than BR, at 57.3% and 4.6% (hazard ratio [HR], 0.19; 95% CI, 0.14 to 0.25), and 85.3% and 66.8% (HR, 0.41; 95% CI, 0.26 to 0.65), respectively. Undetectable MRD (uMRD) at end of combination therapy (EOCT) was associated with superior PFS compared with low MRD positivity (HR, 0.50) and high MRD positivity (HR, 0.15). Patients in the VenR arm who received ibrutinib as their first therapy after progression (n = 12) had a reported response rate of 100% (10 of 10 evaluable patients); patients subsequently treated with a venetoclax-based regimen (n = 14) had a reported response rate of 55% (six of 11 evaluable patients). With VenR, the uMRD rate at end of treatment (EOT) was lower in patients with GC than in those without GC (<i>P</i> = 0.042); higher GC was associated with shorter PFS. Higher MRD positivity rates were seen with <i>BIRC3</i> and <i>BRAF</i> mutations at EOCT and with <i>TP53, NOTCH1, XPO1,</i> and <i>BRAF</i> mutations at EOT. <b>Conclusion:</b> Efficacy benefits with fixed-duration VenR are sustained and particularly durable in patients who achieve uMRD. Salvage therapy with ibrutinib after VenR achieved high response rates. Genetic mutations and GC affected MRD rates and PFS. <b>Trial registration:</b> ClinicalTrials.gov NCT02005471.

scholarly journals The FKBP4 Gene, Encoding a Regulator of the Androgen Receptor Signaling Pathway, Is a Novel Candidate Gene for Androgen Insensitivity Syndrome

2020 ◽  
Vol 21 (21) ◽  
pp. 8403
Author(s):  
Erkut Ilaslan ◽  
Renata Markosyan ◽  
Patrick Sproll ◽  
Brian J. Stevenson ◽  
Malgorzata Sajek ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Signaling Pathway ◽  
Gene Mutation ◽  
Gene Mutations ◽  
Androgen Insensitivity Syndrome ◽  
Homologous Gene ◽  
Gene Encoding ◽  
Androgen Insensitivity ◽  
Disorder Of Sexual Development ◽  
Partial Androgen Insensitivity Syndrome

Androgen insensitivity syndrome (AIS), manifesting incomplete virilization in 46,XY individuals, is caused mostly by androgen receptor (AR) gene mutations. Therefore, a search for AR mutations is a routine approach in AIS diagnosis. However, some AIS patients lack AR mutations, which complicates the diagnosis. Here, we describe a patient suffering from partial androgen insensitivity syndrome (PAIS) and lacking AR mutations. The whole exome sequencing of the patient and his family members identified a heterozygous FKBP4 gene mutation, c.956T>C (p.Leu319Pro), inherited from the mother. The gene encodes FKBP prolyl isomerase 4, a positive regulator of the AR signaling pathway. This is the first report describing a FKBP4 gene mutation in association with a human disorder of sexual development (DSD). Importantly, the dysfunction of a homologous gene was previously reported in mice, resulting in a phenotype corresponding to PAIS. Moreover, the Leu319Pro amino acid substitution occurred in a highly conserved position of the FKBP4 region, responsible for interaction with other proteins that are crucial for the AR functional heterocomplex formation and therefore the substitution is predicted to cause the disease. We proposed the FKBP4 gene as a candidate AIS gene and suggest screening that gene for the molecular diagnosis of AIS patients lacking AR gene mutations.

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