Mutational analysis of phospholipase C epsilon 1 gene in Egyptian children with steroid-resistant nephrotic syndrome (original) (raw)
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Molecular medicine reports, 2018
Nephrotic syndrome (NS) represents a heterogeneous group of kidney disorders characterized by excessive proteinuria, hypoalbuminemia and edema. Defects in the filtration barrier of the glomeruli results in the development of NS. The genetic cause of NS remains to be fully elucidated. However, previous studies based on positional cloning of genes mutated in NS have provided limited insight into the pathogenesis of this disease. Mutations in phospholipase C ε‑1 (PLCE1) have been reported as a cause of early onset NS characterized by histology of diffuse mesangial sclerosis. In the present study, the underlying cause of NS in a consanguineous family was identified. Clinical and molecular aspects of a consanguineous Saudi family comprised of five individuals with steroid resistant NS were examined. Seven healthy individuals from the same family were also studied. Whole exome sequencing (WES) was performed to detect the genetic defect underlying NS. WES identified a homozygous novel inse...
Mutational analysis of the PLCE1 gene in steroid resistant nephrotic syndrome
Journal of Medical Genetics, 2010
Background: Mutations in the PLCE1 gene encoding phospholipase C epsilon 1 (PLCε1) have been recently described in patients with early-onset nephrotic syndrome (NS) and diffuse mesangial sclerosis (DMS). In addition, two cases of PLCE1 mutations associated with focal segmental glomerulosclerosis (FSGS) and later NS onset have been reported.
Genetic mutation in Egyptian children with steroid-resistant nephrotic syndrome
Journal of the Formosan Medical Association, 2017
Background/Purpose: Nephrotic syndrome is the commonest etiology of proteinuria in children. Steroid-resistant nephrotic syndrome (SRNS) is defined by resistance to standard steroid therapy, and it continues to be one of the most intractable etiologies of renal failure. Molecular studies discovered specialized molecules in podocytes that play a role in proteinuria. Mutations in NPHS2 that encodes for podocin constitute a frequent cause of SRNS worldwide. This study aimed to screen for podocin mutations in SRNS Egyptian children and their parents. Methods: Our study included patients from 10 unrelated Egyptian families diagnosed with SRNS. Mutational analysis of the NPHS2 gene was performed by polymerase chain reaction amplification of the whole coding region of the gene and direct sequencing. Results: Positive consanguinity was detected in five cases, and four of them had a positive family history of SRNS in a family member. Mutational analysis of NPHS2 revealed pathogenic mutations in four cases (40%) including a novel missense in one patient (c.1A>T; p.M1L). Conclusion: Our study concludes that mutations of NPHS2 gene are common among Egyptian children with SRNS. We support a model where ethnicity plays an important role in specific NPHS2 mutations, since a novel mutation was found in one patient in this study. Future study on a large number of Egyptian patients with SRNS is warranted to identify the actual genetic
Phospholipase C-Gamma 2 Activity in Familial Steroid-Sensitive Nephrotic Syndrome
Pediatric Research, 2018
BACKGROUND: Familial Steroid-sensitive Nephrotic Syndrome (SSNS) is rare, complicating the identification of candidate genes. A recent population-based approach study of SSNS identified HLA-DQA1 and Phospholipase C-Gamma 2 (PLCG2) missense coding variants as candidate loci. PLCG2 is a signaling molecule regulated by phosphorylation and is critical for Ca 2+ flux in cells of the immune system. METHODS: In order to detect a candidate gene for familial SSNS, we conducted an whole-exome sequencing in a pedigree consisting of two healthy parents, two non-identical twin brothers with SSNS, and a healthy young sibling. Flow cytometric assays were conducted to investigate the effects of the identified PLCG2 rare variants on B cell receptor-mediated PLCG2 tyrosine 759 phosphorylation, as well as on Ca 2+ flux. RESULTS: Two missense rare variants in the PLCG2 gene were detected in the affected twins. An increase in tyrosine phosphorylation of PLCG2 as well as more rapid Ca 2+ flux were noted in response to stimulation in the affected twins compared to their parents. CONCLUSIONS: Rare variants in PLCG2 segregated with disease in familial SSNS. Functional studies suggest the combined rare variants result in a gain of function in PLCG2 activity. Taken together, these results support PLCG2 as a possible candidate locus for familial SSNS.
Molecular genetic analysis of Steroid Resistant Nephrotic Syndrome: Detection of a novel mutation
ABSTRACTBackground: Nephrotic syndrome is one of the most common kidney diseases in childhood. About 20% of children are steroid-resistant NS (SRNS) which progress to end-stage renal disease (ESRD). More than 53 genes are associated with SRNS which represent the genetic heterogeneity of SRNS. This study was aimed to screen disease causing mutations within NPHS1 and NPHS2 and evaluate new potential variants in other genes.Method: In first phase of study, 25 patients with SRNS were analyzed for NPHS1 (exon 2, 26) and all exons of NPHS2 genes by Sanger sequencing. In the second phase, whole exome sequencing was performed on 10 patients with no mutations in NPHS1 and NPHS2.Result: WES analysis revealed a novel mutation in FAT1 (c.10570C>A; Q3524K). We identified 4 pathogenic mutations, located in exon 4 and 5 of NPHS2 gene in 20% of patients (V180M, P118L, R168C and Leu156Phe). Also our study has contributed to the descriptions of previously known pathogenic mutations across WT1 (R20...
Nature Genetics, 2006
Nephrotic syndrome, a malfunction of the kidney glomerular filter, leads to proteinuria, edema and, in steroid-resistant nephrotic syndrome, end-stage kidney disease. Using positional cloning, we identified mutations in the phospholipase C epsilon gene (PLCE1) as causing early-onset nephrotic syndrome with end-stage kidney disease. Kidney histology of affected individuals showed diffuse mesangial sclerosis (DMS). Using immunofluorescence, we found PLCe1 expression in developing and mature glomerular podocytes and showed that DMS represents an arrest of normal glomerular development. We identified IQ motif-containing GTPase-activating protein 1 as a new interaction partner of PLCe1. Two siblings with a missense mutation in an exon encoding the PLCe1 catalytic domain showed histology characteristic of focal segmental glomerulosclerosis. Notably, two other affected individuals responded to therapy, making this the first report of a molecular cause of nephrotic syndrome that may resolve after therapy. These findings, together with the zebrafish model of human nephrotic syndrome generated by plce1 knockdown, open new inroads into pathophysiology and treatment mechanisms of nephrotic syndrome.
Rapid Detection of Monogenic Causes of Childhood-Onset Steroid-Resistant Nephrotic Syndrome
Clinical Journal of the American Society of Nephrology, 2014
Background and objectives In steroid-resistant nephrotic syndrome (SRNS), .21 single-gene causes are known. However, mutation analysis of all known SRNS genes is time and cost intensive. This report describes a new highthroughput method of mutation analysis using a PCR-based microfluidic technology that allows rapid simultaneous mutation analysis of 21 single-gene causes of SRNS in a large number of individuals.
PubMed, 2013
Introduction: Mutations in podocin (NPHS2) gene have the key role in the pathogenesis of steroid-resistant nephrotic syndrome (SRNS) in children, but data is scarce regarding their prevalence and natural course among different all ethnic groups. This study was aimed to demonstrate the spectrum of NPHS2 mutations in children with SRNS and to compare the clinical course of disease in patients with and without mutation. Materials and methods: All 8 exons of NPHS2 were sequenced in 99 children, including 49 with SRNS and 50 with steroid-sensitive nephrotic syndrome (control group) by DNA sequencing. Results: The prevalence rates of NPHS2 gene mutation among children with SRNS and SSNS were 31% and 4%, respectively. The prevalence rates of mutation among familial and sporadic forms were 57% and 26%, respectively. Thirty-three percent of the children experienced recurrence of primary disease after kidney transplantation, none of whom had a mutation. The clinical response to treatment was poorer in children with mutation in comparison with patients without mutation (12% versus 32%, respectively; odds ratio, 3.29, 95% confidence interval, 0.40 to 25.64). Patients with and without mutation could not be differentiated by demographic and histological features, glomerular filtration rate at onset, hypertension, progression to end-stage renal disease, and proteinuria. Conclusions: Mutations of NPHS2 gene are frequent among Iranian children with SRNS. Regarding similar clinical features in patients with and without mutation and poor response to pharmacotherapy in patients with mutation, a molecular approach might be necessary for different treatment plans and prediction of prognosis.
Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic …
Nature genetics, 2006
Nephrotic syndrome, a malfunction of the kidney glomerular filter, leads to proteinuria, edema and, in steroid-resistant nephrotic syndrome, end-stage kidney disease. Using positional cloning, we identified mutations in the phospholipase C epsilon gene (PLCE1) as causing early-onset nephrotic syndrome with end-stage kidney disease. Kidney histology of affected individuals showed diffuse mesangial sclerosis (DMS). Using immunofluorescence, we found PLCe1 expression in developing and mature glomerular podocytes and showed that DMS represents an arrest of normal glomerular development. We identified IQ motif-containing GTPase-activating protein 1 as a new interaction partner of PLCe1. Two siblings with a missense mutation in an exon encoding the PLCe1 catalytic domain showed histology characteristic of focal segmental glomerulosclerosis. Notably, two other affected individuals responded to therapy, making this the first report of a molecular cause of nephrotic syndrome that may resolve after therapy. These findings, together with the zebrafish model of human nephrotic syndrome generated by plce1 knockdown, open new inroads into pathophysiology and treatment mechanisms of nephrotic syndrome.