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1.
Pediatr Nephrol ; 2024 Jun 21.
Article in English | MEDLINE | ID: mdl-38904753

ABSTRACT

BACKGROUND: Steroid-resistant nephrotic syndrome is the second leading cause of chronic kidney disease among patients < 25 years of age. Through exome sequencing, identification of > 65 monogenic causes has revealed insights into disease mechanisms of nephrotic syndrome (NS). METHODS: To elucidate novel monogenic causes of NS, we combined homozygosity mapping with exome sequencing in a worldwide cohort of 1649 pediatric patients with NS. RESULTS: We identified homozygous missense variants in MYO1C in two unrelated children with NS (c.292C > T, p.R98W; c.2273 A > T, p.K758M). We evaluated publicly available kidney single-cell RNA sequencing datasets and found MYO1C to be predominantly expressed in podocytes. We then performed structural modeling for the identified variants in PyMol using aligned shared regions from two available partial structures of MYO1C (4byf and 4r8g). In both structures, calmodulin, a common regulator of myosin activity, is shown to bind to the IQ motif. At both residue sites (K758; R98), there are ion-ion interactions stabilizing intradomain and ligand interactions: R98 binds to nearby D220 within the myosin motor domain and K758 binds to E14 on a calmodulin molecule. Variants of these charged residues to non-charged amino acids could ablate these ionic interactions, weakening protein structure and function establishing the impact of these variants. CONCLUSION: We here identified recessive variants in MYO1C as a potential novel cause of NS in children.

3.
Cureus ; 15(1): e34332, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36865980

ABSTRACT

We report the case of an adolescent girl with frequent hospital admissions for severe eczematous skin rashes with recurrent epistaxis and chest infections. Investigations revealed persistent severely elevated serum total immunoglobulin E (IgE) levels but normal levels of other immunoglobulins, suggesting hyper-IgE syndrome. The first skin biopsy revealed superficial dermatophytic dermatitis (tinea corpora). Another biopsy performed after six months revealed a prominent basement membrane with dermal mucin, suggesting an underlying autoimmune disease. Her condition was complicated by proteinuria, hematuria, hypertension, and edema. A kidney biopsy revealed class IV lupus nephritis, according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS). Based on the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria, she was diagnosed with systemic lupus erythematosus (SLE). She was first administered with intravenous pulse methylprednisolone (600 mg/m2) for three consecutive days, followed by oral prednisolone (40 mg/m2) daily, mycophenolate mofetil tablets (600 mg/m2/dose) twice daily, hydroxychloroquine (200 mg) once daily, and three classes of antihypertensive medications. She maintained normal renal functions with no lupus morbidity for 24 months, then rapidly progressed to end-stage kidney disease, and was then started on three to four sessions of regular hemodialysis per week. Hyper-IgE is known to be a marker of immune dysregulation as it facilitates the generation of immune complexes (ICs) that mediate lupus nephritis and juvenile SLE. Regardless of the different factors that are impacting the production of IgE, the present case illustrated that juvenile patients with SLE may have increased IgE levels, indicating that higher IgE levels might have a role in lupus pathogenesis and prognosis. The mechanisms regarding the increased levels of IgE in subjects with lupus need further investigation. Further studies are thus required to assess the incidence, prognosis, and possible new specific management for hyper-IgE in juvenile SLE.

4.
Eur Urol Open Sci ; 44: 106-112, 2022 Oct.
Article in English | MEDLINE | ID: mdl-36185583

ABSTRACT

Background: Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease among children and adults younger than 30 yr. In our previous study, whole-exome sequencing (WES) identified a known monogenic cause of isolated or syndromic CAKUT in 13% of families with CAKUT. However, WES has limitations and detection of copy number variations (CNV) is technically challenging, and CNVs causative of CAKUT have previously been detected in up to 16% of cases. Objective: To detect CNVs causing CAKUT in this WES cohort and increase the diagnostic yield. Design setting and participants: We performed a genome-wide single nucleotide polymorphism (SNP)-based CNV analysis on the same CAKUT cohort for whom WES was previously conducted. Outcome measurements and statistical analysis: We evaluated and classified the CNVs using previously published predefined criteria. Results and limitations: In a cohort of 170 CAKUT families, we detected a pathogenic CNV known to cause CAKUT in nine families (5.29%, 9/170). There were no competing variants on genome-wide CNV analysis or WES analysis. In addition, we identified novel likely pathogenic CNVs that may cause a CAKUT phenotype in three of the 170 families (1.76%). Conclusions: CNV analysis in this cohort of 170 CAKUT families previously examined via WES increased the rate of diagnosis of genetic causes of CAKUT from 13% on WES to 18% on WES + CNV analysis combined. We also identified three candidate loci that may potentially cause CAKUT. Patient summary: We conducted a genetics study on families with congenital anomalies of the kidney and urinary tract (CAKUT). We identified gene mutations that can explain CAKUT symptoms in 5.29% of the families, which increased the percentage of genetic causes of CAKUT to 18% from a previous study, so roughly one in five of our patients with CAKUT had a genetic cause. These analyses can help patients with CAKUT and their families in identifying a possible genetic cause.

5.
Am J Med Genet A ; 188(5): 1355-1367, 2022 05.
Article in English | MEDLINE | ID: mdl-35040250

ABSTRACT

Spina bifida (SB) is the second most common nonlethal congenital malformation. The existence of monogenic SB mouse models and human monogenic syndromes with SB features indicate that human SB may be caused by monogenic genes. We hypothesized that whole exome sequencing (WES) allows identification of potential candidate genes by (i) generating a list of 136 candidate genes for SB, and (ii) by unbiased exome-wide analysis. We generated a list of 136 potential candidate genes from three categories and evaluated WES data of 50 unrelated SB cases for likely deleterious variants in 136 potential candidate genes, and for potential SB candidate genes exome-wide. We identified 6 likely deleterious variants in 6 of the 136 potential SB candidate genes in 6 of the 50 SB cases, whereof 4 genes were derived from mouse models, 1 gene was derived from human nonsyndromic SB, and 1 gene was derived from candidate genes known to cause human syndromic SB. In addition, by unbiased exome-wide analysis, we identified 12 genes as potential candidates for SB. Identification of these 18 potential candidate genes in larger SB cohorts will help decide which ones can be considered as novel monogenic causes of human SB.


Subject(s)
Exome , Spinal Dysraphism , Animals , Disease Models, Animal , Exome/genetics , Humans , Mice , Spinal Dysraphism/genetics , Exome Sequencing
6.
Indian J Pediatr ; 89(1): 67-70, 2022 Jan.
Article in English | MEDLINE | ID: mdl-34633631

ABSTRACT

Bladder dysfunction in children is common, the most frequent underlying causes are neurologic bladder (NB), dysfunctional voiding syndrome (DVS), and the valve bladder syndrome (VBS). The aim of this study was to determine the 10-y survival rate and the associated morbidities in children with bladder dysfunction. One hundred ninety-nine children were included in the study; 60 with VBS, 75 DVS, and 64 NB. The mean age was 44 mo (CI: 37-50.9) and mean GFR 50.1 (CI 44.6-55.6) mL/min/1.73m2. The 10-y survival rate was 89%. Compared with patients with VBS, the mortality was 11 times higher among patients with NB (p = 0.02) but not significantly higher than patients with DVS (p = 0.2). GFR < 15 mL/min/1.73 m2 increases mortality rate by 6 times compared with normal GFR (p = 0.007). Late age at presentation (> 5 y) increases mortality risk and/or the need for renal replacement therapy (RRT) by almost 5 times (p = 0.013). It was concluded that the etiology of bladder dysfunction, baseline GFR, and the age at presentation significantly influence the survival rate and morbidities.


Subject(s)
Urinary Bladder Diseases , Urinary Bladder , Adult , Child , Humans , Urinary Bladder Diseases/epidemiology , Urinary Bladder Diseases/etiology
7.
Genet Med ; 24(2): 307-318, 2022 02.
Article in English | MEDLINE | ID: mdl-34906515

ABSTRACT

PURPOSE: Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the leading cause of chronic kidney disease in children. In total, 174 monogenic causes of isolated or syndromic CAKUT are known. However, syndromic features may be overlooked when the initial clinical diagnosis of CAKUT is made. We hypothesized that the yield of a molecular genetic diagnosis by exome sequencing (ES) can be increased by applying reverse phenotyping, by re-examining the case for signs/symptoms of the suspected clinical syndrome that results from the genetic variant detected by ES. METHODS: We conducted ES in an international cohort of 731 unrelated families with CAKUT. We evaluated ES data for variants in 174 genes, in which variants are known to cause isolated or syndromic CAKUT. In cases in which ES suggested a previously unreported syndromic phenotype, we conducted reverse phenotyping. RESULTS: In 83 of 731 (11.4%) families, we detected a likely CAKUT-causing genetic variant consistent with an isolated or syndromic CAKUT phenotype. In 19 of these 83 families (22.9%), reverse phenotyping yielded syndromic clinical findings, thereby strengthening the genotype-phenotype correlation. CONCLUSION: We conclude that employing reverse phenotyping in the evaluation of syndromic CAKUT genes by ES provides an important tool to facilitate molecular genetic diagnostics in CAKUT.


Subject(s)
Urinary Tract , Urogenital Abnormalities , Alleles , Exome/genetics , Humans , Kidney/abnormalities , Urogenital Abnormalities/genetics , Vesico-Ureteral Reflux
8.
JCI Insight ; 7(2)2022 01 25.
Article in English | MEDLINE | ID: mdl-34874915

ABSTRACT

We performed next-generation sequencing in patients with familial steroid-sensitive nephrotic syndrome (SSNS) and identified a homozygous segregating variant (p.H310Y) in the gene encoding clavesin-1 (CLVS1) in a consanguineous family with 3 affected individuals. Knockdown of the clavesin gene in zebrafish (clvs2) produced edema phenotypes due to disruption of podocyte structure and loss of glomerular filtration barrier integrity that could be rescued by WT CLVS1 but not the p.H310Y variant. Analysis of cultured human podocytes with CRISPR/Cas9-mediated CLVS1 knockout or homozygous H310Y knockin revealed deficits in clathrin-mediated endocytosis and increased susceptibility to apoptosis that could be rescued with corticosteroid treatment, mimicking the steroid responsiveness observed in patients with SSNS. The p.H310Y variant also disrupted binding of clavesin-1 to α-tocopherol transfer protein, resulting in increased reactive oxygen species (ROS) accumulation in CLVS1-deficient podocytes. Treatment of CLVS1-knockout or homozygous H310Y-knockin podocytes with pharmacological ROS inhibitors restored viability to control levels. Taken together, these data identify CLVS1 as a candidate gene for SSNS, provide insight into therapeutic effects of corticosteroids on podocyte cellular dynamics, and add to the growing evidence of the importance of endocytosis and oxidative stress regulation to podocyte function.


Subject(s)
Carrier Proteins/genetics , Endocytosis , Nephrotic Syndrome , Oxidative Stress , Podocytes , Adrenal Cortex Hormones , Animals , Apoptosis/drug effects , CRISPR-Cas Systems/genetics , Cells, Cultured , Endocytosis/drug effects , Endocytosis/genetics , Gene Knockout Techniques , Genetic Association Studies , High-Throughput Nucleotide Sequencing/methods , Humans , Nephrotic Syndrome/drug therapy , Nephrotic Syndrome/genetics , Nephrotic Syndrome/metabolism , Nephrotic Syndrome/pathology , Oxidative Stress/drug effects , Oxidative Stress/genetics , Podocytes/drug effects , Podocytes/metabolism , Reactive Oxygen Species/antagonists & inhibitors , Zebrafish , Zebrafish Proteins
9.
Saudi Med J ; 42(8): 869-877, 2021 Aug.
Article in English | MEDLINE | ID: mdl-34344811

ABSTRACT

OBJECTIVES: To review voiding dysfunction caused by 3 different etiologies; dysfunction voiding syndrome (DVS), neurogenic bladder secondary to spinal dysraphisim (NB), and valve bladder syndrome (VBS). METHODS: A single-center retrospective study on children with voiding dysfunction followed up at King Abdulaziz University Hospital, Jeddah, Saudi Arabia from 2005 to 2017. RESULTS: One hundred and ninety-nine children (67.3% boys) were included: Group 1 (n=75, DVS), Group 2 (n=64, NB), and Group 3 (n=60, VBS). Further classification according to the age at presentation; infants (46%), toddlers (27%) and school aged (28%). Management categories: 31% children needed observation only, 25% needed clean intermittent catheterization (CIC), 13% needed only surgery and 31% needed both surgery and CIC. Associated comorbidities: hydronephrosis (81%), vesicoureteral reflux (47%), pyelonephritis (37%) and renal scar (60%), all have negative impact on estimated glomerular filtration rate (eGFR). Urodynamic studies revealed poor bladder compliance in 57.6% and atonic bladder in 1.1%, progression to chronic kidney disease (22%), commenced on renal replacement therapy 11.5% and 4% died with ESKD. Overall improvement in the last eGFR is observed (p<0.001), but VBS group was the least to improve (p=0.021). There was a negative correlation between the last eGFR and age at presentation (p=0.002). CONCLUSION: Early diagnosis and management of childhood voiding dysfunction was associated with better prognosis. Children managed conservatively have better preservation of kidney function than those who needed surgery.


Subject(s)
Urinary Bladder Diseases , Urinary Bladder, Neurogenic , Vesico-Ureteral Reflux , Child , Female , Humans , Infant , Male , Retrospective Studies
10.
Am J Med Genet A ; 185(10): 3005-3011, 2021 10.
Article in English | MEDLINE | ID: mdl-34145744

ABSTRACT

WNT9B plays a key role in the development of the mammalian urogenital system. It is essential for the induction of mesonephric and metanephric tubules, the regulation of renal tubule morphogenesis, and the regulation of renal progenitor cell expansion and differentiation. To our knowledge, WNT9B has not been associated with renal defects in humans; however, WNT9B-/- mice have renal agenesis/hypoplasia and reproductive tract abnormalities. We report four individuals from two unrelated consanguineous families with bilateral renal agenesis/hypoplasia/dysplasia and homozygous variants in WNT9B. The proband from Family 1 has bilateral renal cystic dysplasia and chronic kidney disease. He has two deceased siblings who presented with bilateral renal hypoplasia/agenesis. The three affected family members were homozygous for a missense variant in WNT9B (NM_003396.2: c.949G>A/p.(Gly317Arg)). The proband from Family 2 has renal hypoplasia/dysplasia, chronic kidney disease, and is homozygous for a nonsense variant in WNT9B (NM_003396.2: c.11dupC/p.(Pro5Alafs*52)). Two of her siblings died in the neonatal period, one confirmed to be in the context of oligohydramnios. The proband's unaffected brother is also homozygous for the nonsense variant in WNT9B, suggesting nonpenetrance. We propose a novel association of WNT9B and renal anomalies in humans. Further study is needed to delineate the contribution of WNT9B to genitourinary anomalies in humans.


Subject(s)
Congenital Abnormalities/genetics , Kidney Diseases/congenital , Kidney/abnormalities , Urogenital Abnormalities/genetics , Wnt Proteins/genetics , Animals , Child , Congenital Abnormalities/pathology , Female , Homozygote , Humans , Infant , Kidney/pathology , Kidney Diseases/genetics , Kidney Diseases/pathology , Kidney Tubules/growth & development , Kidney Tubules/pathology , Male , Mice , Pregnancy , Urinary Tract/growth & development , Urinary Tract/metabolism , Urinary Tract/pathology , Urogenital Abnormalities/diagnosis , Urogenital Abnormalities/pathology
11.
Kidney Int Rep ; 6(2): 472-483, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33615072

ABSTRACT

INTRODUCTION: Most of the approximately 60 genes that if mutated cause steroid-resistant nephrotic syndrome (SRNS) are highly expressed in the glomerular podocyte, rendering SRNS a "podocytopathy." METHODS: We performed whole-exome sequencing (WES) in 1200 nephrotic syndrome (NS) patients. RESULTS: We discovered homozygous truncating and homozygous missense mutation in SYNPO2 (synaptopodin-2) (p.Lys1124∗ and p.Ala1134Thr) in 2 patients with childhood-onset NS. We found SYNPO2 expression in both podocytes and mesangial cells; however, notably, immunofluorescence staining of adult human and rat kidney cryosections indicated that SYNPO2 is localized mainly in mesangial cells. Subcellular localization studies reveal that in these cells SYNPO2 partially co-localizes with α-actinin and filamin A-containing F-actin filaments. Upon transfection in mesangial cells or podocytes, EGFP-SYNPO2 co-localized with α-actinin-4, which gene is mutated in autosomal dominant SRNS in humans. SYNPO2 overexpression increases mesangial cell migration rate (MMR), whereas shRNA knockdown reduces MMR. Decreased MMR was rescued by transfection of wild-type mouse Synpo2 cDNA but only partially by cDNA representing mutations from the NS patients. The increased mesangial cell migration rate (MMR) by SYNPO2 overexpression was inhibited by ARP complex inhibitor CK666. SYNPO2 shRNA knockdown in podocytes decreased active Rac1, which was rescued by transfection of wild-type SYNPO2 cDNA but not by cDNA representing any of the 2 mutant variants. CONCLUSION: We show that SYNPO2 variants may lead to Rac1-ARP3 dysregulation, and may play a role in the pathogenesis of nephrotic syndrome.

12.
Saudi J Kidney Dis Transpl ; 32(6): 1628-1636, 2021.
Article in English | MEDLINE | ID: mdl-35946275

ABSTRACT

Advanced chronic kidney disease with mineral and bone disorder have a significant obstacles to control serum bone profile [serum intact parathyroid hormone (iPTH), calcium and phosphorus] which subsequently have major effect on optimal bone strength, final adult height, and cardiovascular health. A retrospective, observational study, including a total of 36 children with end-stage kidney disease (ESKD). Fourteen children who were prescribed cinacalcet had been compared with the remaining 22 children who were managed with standard care. We report the efficacy and safety of cinacalcet for treatment of refractory secondary hyperparathyroidism (SHPT) in children with ESKD. After 6 months of cinacalcet treatment, the mean level of iPTH serum level decreased by 56% from 202 pmol/L [95% confidence interval (CI): 150-253] to 88 pmol/L (95% CI: 41-136), compared to the change observed in the control group (P <0.001). None of our patients reported serious adverse effects or developed hypocalcemia. Cinacalcet could be an effective and safe alternative to treat severe SHPT in children with ESKD. Further long-term and large-scale studies are necessary to confirm its safety and efficacy.


Subject(s)
Hyperparathyroidism, Secondary , Kidney Failure, Chronic , Adult , Calcimimetic Agents/adverse effects , Calcium , Child , Cinacalcet/adverse effects , Humans , Hyperparathyroidism, Secondary/diagnosis , Hyperparathyroidism, Secondary/drug therapy , Hyperparathyroidism, Secondary/etiology , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/diagnosis , Parathyroid Hormone , Phosphorus , Renal Dialysis/adverse effects , Retrospective Studies , Treatment Outcome
13.
Nephrol Dial Transplant ; 36(2): 237-246, 2021 01 25.
Article in English | MEDLINE | ID: mdl-33097957

ABSTRACT

BACKGROUND: An underlying monogenic cause of early-onset chronic kidney disease (CKD) can be detected in ∼20% of individuals. For many etiologies of CKD manifesting before 25 years of age, >200 monogenic causative genes have been identified to date, leading to the elucidation of mechanisms of renal pathogenesis. METHODS: In 51 families with echogenic kidneys and CKD, we performed whole-exome sequencing to identify novel monogenic causes of CKD. RESULTS: We discovered a homozygous truncating mutation in the transcription factor gene transcription factor CP2-like 1 (TFCP2L1) in an Arabic patient of consanguineous descent. The patient developed CKD by the age of 2 months and had episodes of severe hypochloremic, hyponatremic and hypokalemic alkalosis, seizures, developmental delay and hypotonia together with cataracts. We found that TFCP2L1 was localized throughout kidney development particularly in the distal nephron. Interestingly, TFCP2L1 induced the growth and development of renal tubules from rat mesenchymal cells. Conversely, the deletion of TFCP2L1 in mice was previously shown to lead to reduced expression of renal cell markers including ion transporters and cell identity proteins expressed in different segments of the distal nephron. TFCP2L1 localized to the nucleus in HEK293T cells only upon coexpression with its paralog upstream-binding protein 1 (UBP1). A TFCP2L1 mutant complementary DNA (cDNA) clone that represented the patient's mutation failed to form homo- and heterodimers with UBP1, an essential step for its transcriptional activity. CONCLUSION: Here, we identified a loss-of-function TFCP2L1 mutation as a potential novel cause of CKD in childhood accompanied by a salt-losing tubulopathy.


Subject(s)
Epithelial-Mesenchymal Transition , Kidney Diseases/etiology , Mutation , Repressor Proteins/genetics , Animals , Child , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Female , HEK293 Cells , Humans , Kidney Diseases/metabolism , Kidney Diseases/pathology , Mice , Mice, Knockout , Rats , Repressor Proteins/metabolism , Single-Cell Analysis , Transcription Factors/genetics , Transcription Factors/metabolism , Exome Sequencing
14.
Genet Med ; 22(10): 1673-1681, 2020 10.
Article in English | MEDLINE | ID: mdl-32475988

ABSTRACT

PURPOSE: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in childhood and adolescence. We aim to identify novel monogenic causes of CAKUT. METHODS: Exome sequencing was performed in 550 CAKUT-affected families. RESULTS: We discovered seven FOXC1 heterozygous likely pathogenic variants within eight CAKUT families. These variants are either never reported, or present in <5 alleles in the gnomAD database with ~141,456 controls. FOXC1 is a causal gene for Axenfeld-Rieger syndrome type 3 and anterior segment dysgenesis 3. Pathogenic variants in FOXC1 have not been detected in patients with CAKUT yet. Interestingly, mouse models for Foxc1 show severe CAKUT phenotypes with incomplete penetrance and variable expressivity. The FOXC1 variants are enriched in the CAKUT cohort compared with the control. Genotype-phenotype correlations showed that Axenfeld-Rieger syndrome or anterior segment dysgenesis can be caused by both truncating and missense pathogenic variants, and the missense variants are located at the forkhead domain. In contrast, for CAKUT, there is no truncating pathogenic variant, and all variants except one are located outside the forkhead domain. CONCLUSION: We thereby expanded the phenotype of FOXC1 pathogenic variants toward involvement of CAKUT, which can potentially be explained by allelism.


Subject(s)
Eye Abnormalities , Urinary Tract , Child , Forkhead Transcription Factors/genetics , Heterozygote , Humans , Kidney , Phenotype
15.
Pediatr Nephrol ; 35(8): 1445-1453, 2020 08.
Article in English | MEDLINE | ID: mdl-32337638

ABSTRACT

BACKGROUND: Approximately 50% of children with steroid-sensitive nephrotic syndrome (SSNS) will suffer from frequent relapses or steroid dependency, prompting the use of so-called steroid-sparing drugs. In this pilot study, we compare the efficacy and safety of rituximab to oral cyclophosphamide as first-line steroid-sparing medications. METHODS: A prospective open-label non-randomized study of children with frequent relapsing or steroid-dependant SSNS. Exclusion criteria were steroid-resistant disease, prescription of immunosuppressive agents other than prednisolone or levamisole, evidence of impaired kidney function, leucopenia, or active infection. The recruited children were allocated either to the oral cyclophosphamide (3 mg/kg/day for 8 weeks) or intravenous rituximab treatment (two doses of 375 mg/m2/dose, 2 weeks apart) and were monitored for relapses and side effects for 12 months. RESULTS: Forty-six subjects were included from two centers; 27 received cyclophosphamide and 19 received rituximab. One-year relapse-free survival was reached in 17 (58.6%) patients treated with cyclophosphamide compared to 16 (84.2%) with rituximab (adjusted HR 0.36; 95% CI 0.09-1.45; p = 0.151). The mean interval to relapse was 6.9 months in the cyclophosphamide group (N = 10) and 6.3 months in the rituximab group (N = 3). Both treatments were associated with a significant (p < 0.001) reduction in prescribed dose of oral alternate-day steroid from 1.02 to 0.36 mg/kg (cyclophosphamide) and 0.86 to 0.08 mg/kg (rituximab). Importantly, a significantly (p = 0.003) higher percentage of patients achieved complete withdrawal of steroid within 3 months of commencing study treatment in the rituximab (73.7%) versus cyclophosphamide (29.6%) group. Transient leucopenia was the most frequent adverse effect observed in the cyclophosphamide group (18.5%) and one patient (3.4%) had acute hepatotoxicity besides severe leucopenia and neutropenia in the 7th week of treatment with complete recovery with the withdrawal of cyclophosphamide and maintenance of remission. A minor infusion-related reaction in the form of a generalized macular skin rash was observed in one patient (5%) in the rituximab group. CONCLUSIONS: Rituximab is non-inferior to cyclophosphamide and safe as a first-line steroid-sparing agent in children with SSNS. A larger multicenter study is required to assess superiority over cyclophosphamide. Graphical abstract.


Subject(s)
Cyclophosphamide/administration & dosage , Immunosuppressive Agents/administration & dosage , Nephrotic Syndrome/drug therapy , Rituximab/administration & dosage , Child , Child, Preschool , Female , Humans , Male , Pilot Projects , Prospective Studies , Remission Induction/methods
16.
Am J Hum Genet ; 105(6): 1286-1293, 2019 12 05.
Article in English | MEDLINE | ID: mdl-31708116

ABSTRACT

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life, and in utero obstruction to urine flow is a frequent cause of secondary upper urinary tract malformations. Here, using whole-exome sequencing, we identified three different biallelic mutations in CHRNA3, which encodes the α3 subunit of the nicotinic acetylcholine receptor, in five affected individuals from three unrelated families with functional lower urinary tract obstruction and secondary CAKUT. Four individuals from two families have additional dysautonomic features, including impaired pupillary light reflexes. Functional studies in vitro demonstrated that the mutant nicotinic acetylcholine receptors were unable to generate current following stimulation with acetylcholine. Moreover, the truncating mutations p.Thr337Asnfs∗81 and p.Ser340∗ led to impaired plasma membrane localization of CHRNA3. Although the importance of acetylcholine signaling in normal bladder function has been recognized, we demonstrate for the first time that mutations in CHRNA3 can cause bladder dysfunction, urinary tract malformations, and dysautonomia. These data point to a pathophysiologic sequence by which monogenic mutations in genes that regulate bladder innervation may secondarily cause CAKUT.


Subject(s)
Autonomic Nervous System Diseases/etiology , Kidney/abnormalities , Mutation , Receptors, Nicotinic/genetics , Urinary Tract/abnormalities , Urogenital Abnormalities/etiology , Adult , Autonomic Nervous System Diseases/genetics , Autonomic Nervous System Diseases/pathology , Female , Follow-Up Studies , Humans , Kidney/pathology , Male , Pedigree , Prognosis , Urinary Tract/pathology , Urogenital Abnormalities/genetics , Urogenital Abnormalities/pathology , Young Adult
17.
Hum Genet ; 138(10): 1105-1115, 2019 Oct.
Article in English | MEDLINE | ID: mdl-31230195

ABSTRACT

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease (~ 45%) that manifests before 30 years of age. The genetic locus containing COL4A1 (13q33-34) has been implicated in vesicoureteral reflux (VUR), but mutations in COL4A1 have not been reported in CAKUT. We hypothesized that COL4A1 mutations cause CAKUT in humans. We performed whole exome sequencing (WES) in 550 families with CAKUT. As negative control cohorts we used WES sequencing data from patients with nephronophthisis (NPHP) with no genetic cause identified (n = 257) and with nephrotic syndrome (NS) due to monogenic causes (n = 100). We identified a not previously reported heterozygous missense variant in COL4A1 in three siblings with isolated VUR. When examining 549 families with CAKUT, we identified nine additional different heterozygous missense mutations in COL4A1 in 11 individuals from 11 unrelated families with CAKUT, while no COL4A1 mutations were identified in a control cohort with NPHP and only one in the cohort with NS. Most individuals (12/14) had isolated CAKUT with no extrarenal features. The predominant phenotype was VUR (9/14). There were no clinical features of the COL4A1-related disorders (e.g., HANAC syndrome, porencephaly, tortuosity of retinal arteries). Whereas COL4A1-related disorders are typically caused by glycine substitutions in the collagenous domain (84.4% of variants), only one variant in our cohort is a glycine substitution within the collagenous domain (1/10). We identified heterozygous COL4A1 mutations as a potential novel autosomal dominant cause of CAKUT that is allelic to the established COL4A1-related disorders and predominantly caused by non-glycine substitutions.


Subject(s)
Collagen Type IV/genetics , Congenital Abnormalities/diagnosis , Congenital Abnormalities/genetics , Kidney/abnormalities , Mutation , Phenotype , Urinary Tract/abnormalities , Alleles , Amino Acid Substitution , Computational Biology/methods , DNA Mutational Analysis , Databases, Genetic , Evolution, Molecular , Female , Genetic Association Studies , Genetic Loci , Genomics/methods , Heterozygote , Humans , Kidney Diseases, Cystic/diagnosis , Kidney Diseases, Cystic/genetics , Male , Nephrotic Syndrome/diagnosis , Nephrotic Syndrome/genetics , Web Browser , Exome Sequencing
18.
World J Pediatr ; 15(2): 198-203, 2019 Apr.
Article in English | MEDLINE | ID: mdl-30721404

ABSTRACT

BACKGROUND: Congenital and infantile nephrotic syndrome (CNS and INS) are rare inherited defects in glomerular filtration involving a variety of gene mutations. This study aimed to analyze all genetic mutations associated with congenital and infantile nephrotic syndrome treated at our institution. We also discussed our different approach secondary to culture and resources. METHODS: A retrospective single-center study of all children diagnosed as NS before the age of 1 year over a duration of over one decade. RESULTS: Twenty-nine children (12 boys) were included in the study. Their median age (range) was 2.4 (0.1-12) months (20 CNS and 9 INS). Consanguinity was present in 90% of children. The genetic analysis' results were only available for 20 children. An underlying causative homozygous mutation was detected in 18 children (90%): NPHS1 (9), NPHS2(2), LAMB2(3), PLCE1(1), WT1(1), and ITSN1 novel mutation (2). One child had heterozygous mutation of NPHS2 and another child had heterozygous mutation of NPHS1 which could not explain the disease. All CNS cases were all managed with intermittent intravenous albumin infusion, ACEi, diuretics, and indomethacin. None of the children were managed by nephrectomy followed by peritoneal dialysis (PD) because of limited resources. Only one child achieved partial remission, while 15 children died at a median (range) age of 5.8 (1.25-29) months. The remaining 14 children were followed up for an average of 36 (3.9-120) months. Three children progressed to end-stage kidney disease and PD was performed in only two children. CONCLUSIONS: NPHS1 is the main underlying cause of CNS and INS in our study population. CNS and INS were associated with high morbidity and mortality.


Subject(s)
Genetic Predisposition to Disease/epidemiology , Intracellular Signaling Peptides and Proteins/genetics , Nephrotic Syndrome/genetics , Nephrotic Syndrome/therapy , Academic Medical Centers , Age Distribution , China , Cohort Studies , Combined Modality Therapy , Disease Progression , Female , Genetic Testing/methods , Humans , Infant , Infant, Newborn , Kidney Failure, Chronic/epidemiology , Kidney Failure, Chronic/physiopathology , Male , Membrane Proteins/genetics , Mutation , Nephrotic Syndrome/diagnosis , Nephrotic Syndrome/epidemiology , Prevalence , Prognosis , Retrospective Studies , Risk Assessment , Sex Distribution
19.
Nephrol Dial Transplant ; 34(3): 485-493, 2019 03 01.
Article in English | MEDLINE | ID: mdl-29534211

ABSTRACT

BACKGROUND: Nephrotic syndrome (NS), a chronic kidney disease, is characterized by significant loss of protein in the urine causing hypoalbuminemia and edema. In general, ∼15% of childhood-onset cases do not respond to steroid therapy and are classified as steroid-resistant NS (SRNS). In ∼30% of cases with SRNS, a causative mutation can be detected in one of 44 monogenic SRNS genes. The gene LAMA5 encodes laminin-α5, an essential component of the glomerular basement membrane. Mice with a hypomorphic mutation in the orthologous gene Lama5 develop proteinuria and hematuria. METHODS: To identify additional monogenic causes of NS, we performed whole exome sequencing in 300 families with pediatric NS. In consanguineous families we applied homozygosity mapping to identify genomic candidate loci for the underlying recessive mutation. RESULTS: In three families, in whom mutations in known NS genes were excluded, but in whom a recessive, monogenic cause of NS was strongly suspected based on pedigree information, we identified homozygous variants of unknown significance (VUS) in the gene LAMA5. While all affected individuals had nonsyndromic NS with an early onset of disease, their clinical outcome and response to immunosuppressive therapy differed notably. CONCLUSION: We here identify recessive VUS in the gene LAMA5 in patients with partially treatment-responsive NS. More data will be needed to determine the impact of these VUS in disease management. However, familial occurrence of disease, data from genetic mapping and a mouse model that recapitulates the NS phenotypes suggest that these genetic variants may be inherited factors that contribute to the development of NS in pediatric patients.


Subject(s)
Exome Sequencing/methods , Immunosuppressive Agents/therapeutic use , Laminin/genetics , Mutation , Nephrotic Syndrome/genetics , Adolescent , Adult , Child , Child, Preschool , DNA Mutational Analysis , Female , Homozygote , Humans , Infant , Infant, Newborn , Male , Nephrotic Syndrome/drug therapy , Nephrotic Syndrome/pathology , Pedigree , Phenotype , Prognosis , Young Adult
20.
BMC Urol ; 18(1): 83, 2018 Sep 26.
Article in English | MEDLINE | ID: mdl-30257657

ABSTRACT

BACKGROUND: Urinary bladder agenesis is a very rare congenital anomaly with very few cases reported in the literature. CASE PRESENTATION: We report a one-month-old baby presenting with ambiguous genitalia and recurrent urinary tract infections. Her clinical course was complicated by renal impairment. Magnetic resonant imaging (MRI) revealed a diagnosis of bladder agenesis with bilateral ectopic insertion of the ureters into the vagina, associated with several other anomalies. The patient underwent bilateral high anterior ureterostomies in an hospital abroad at 5.5 months of age. She then developed ureteral necrosis that had to be corrected with left pyeloplasty and by placing a left nephrostomy tube for drainage. Eventually, the patient's renal function declined, and she developed chronic kidney disease (CKD).The case with its imaging findings and pathogenesis as well as a review of the literature are presented. CONCLUSIONS: Urinary bladder agenesis is a rare congenital condition that can be associated with multiple anomalies. Early diagnosis and therapeutic intervention can prevent progression to chronic kidney disease.


Subject(s)
Abnormalities, Multiple/diagnostic imaging , Choristoma/diagnostic imaging , Ureter , Urinary Bladder/abnormalities , Vaginal Diseases/diagnostic imaging , Cystography , Female , Humans , Infant , Magnetic Resonance Imaging , Urinary Bladder/diagnostic imaging
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