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      Analysis of NPHS2 Gene Mutations in Egyptian Children with Nephrotic Syndrome

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          Abstract

          BACKGROUND:

          Mutations in the NPHS2 genes are the main aetiology of early-onset and familial steroid-resistant nephrotic syndrome (SRNS). The pathogenic NPHS2 mutation together with the p.R229Q variant has been less described among Egyptian children.

          AIM:

          This study aims to determine the mutation of NPHS2 in children with NS and discover the role of p.R229Q variant in SRNS

          METHODS:

          The study included 53 children with NS, and 53 healthy volunteers matched in age and sex controls. The median age at disease onset was 7.3 years. Among NS cases, 31 cases had steroid-sensitive nephrotic syndrome (SSNS) and 22 children with steroid-resistant nephrotic syndrome (SRNS). Polymerase chain reaction amplification of the whole coding region of NPHS2 gene was carried out for its mutational analysis. Restriction digestion testing was carried out after PCR to determine the presence of R229Q polymorphism. Randomly selected samples were re-genotyped by two independent technicians for assessment of Quality control

          RESULTS:

          NS patients showed a significant higher frequency of heterozygous genotype GA (89.5%) compared to control group (10.5%) with increased risk of NS (OR, 12.04; 95% CI, 2.61 to55.38; p < 0.0001). Moreover, SRNS showed a significant higher frequency of GA genotype (68.2%) than the SSNS group (6.5%). The GA genotype was associated with increased risk of SRNS (OR, 31.1; 95% CI, 5.73 to 168.48; P < 0.001) and the A allele was associated with increased risk of SRNS (OR, 15.52; 95% CI, 3.325 to 72.422; P < .001).

          CONCLUSION:

          R229Q polymorphisms are associated with SRNS, and any child with SRNS should be searched for mutations in the NPHS2 gene.

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          NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome.

          N Boute, O Gribouval, S Roselli … (2000)
          Familial idiopathic nephrotic syndromes represent a heterogeneous group of kidney disorders, and include autosomal recessive steroid-resistant nephrotic syndrome, which is characterized by early childhood onset of proteinuria, rapid progression to end-stage renal disease and focal segmental glomerulosclerosis. A causative gene for this disease, NPHS2, was mapped to 1q25-31 and we report here its identification by positional cloning. NPHS2 is almost exclusively expressed in the podocytes of fetal and mature kidney glomeruli, and encodes a new integral membrane protein, podocin, belonging to the stomatin protein family. We found ten different NPHS2 mutations, comprising nonsense, frameshift and missense mutations, to segregate with the disease, demonstrating a crucial role for podocin in the function of the glomerular filtration barrier.
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            Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome.

            Franzisco E Anacleto, Arno Fuchshuber, Friedhelm Hildebrandt … (2004)
            Nephrotic syndrome (NS) represents the association of proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Steroid-resistant NS (SRNS) is defined by primary resistance to standard steroid therapy. It remains one of the most intractable causes of ESRD in the first two decades of life. Mutations in the NPHS2 gene represent a frequent cause of SRNS, occurring in approximately 20 to 30% of sporadic cases of SRNS. On the basis of a very small number of patients, it was suspected that children with homozygous or compound heterozygous mutations in NPHS2 might exhibit primary steroid resistance and a decreased risk of FSGS recurrence after kidney transplantation. To test this hypothesis, NPHS2 mutational analysis was performed with direct sequencing for 190 patients with SRNS from 165 different families and, as a control sample, 124 patients with steroid-sensitive NS from 120 families. Homozygous or compound heterozygous mutations in NPHS2 were detected for 43 of 165 SRNS families (26%). Conversely, no homozygous or compound heterozygous mutations in NPHS2 were observed for the 120 steroid-sensitive NS families. Recurrence of FSGS in a renal transplant was noted for seven of 20 patients with SRNS (35%) without NPHS2 mutations, whereas it occurred for only two of 24 patients with SRNS (8%) with homozygous or compound heterozygous mutations in NPHS2. None of 29 patients with homozygous or compound heterozygous mutations in NPHS2 who were treated with cyclosporine A or cyclophosphamide demonstrated complete remission of NS. It was concluded that patients with SRNS with homozygous or compound heterozygous mutations in NPHS2 do not respond to standard steroid treatment and have a reduced risk for recurrence of FSGS in a renal transplant. Because these findings might affect the treatment plan for childhood SRNS, it might be advisable to perform mutational analysis of NPHS2, if the patient consents, in parallel with the start of the first course of standard steroid therapy.
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              NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence.

              Stefanie Weber, L Esquivel, Sarah M. Tete … (2004)
              Mutations of NPHS2 are causative in familial autosomal-recessive (AR) and sporadic steroid-resistant nephrotic syndrome (SRNS). This study aimed to determine the spectrum of NPHS2 mutations and to establish genotype-phenotype correlations. NPHS2 mutation analysis was performed in 338 patients from 272 families with SRNS: 81 families with AR SRNS, 172 patients with sporadic SRNS, and 19 patients with diffuse mesangial sclerosis (DMS). Twenty-six different pathogenic NPHS2 mutations were detected, including 13 novel mutations. The mutation detection rate was 43% for familial AR and 10.5% for sporadic SRNS, confirming genetic heterogeneity. No pathogenic NPHS2 mutations were found in DMS patients. Age at onset in patients with two pathogenic mutations was earlier, especially in cases with frameshift, truncating, and the R138Q missense mutations. Patients with only one NPHS2 mutation or variant had late-onset NS. Triallelic inheritance was observed in one patient with a homozygous R138Q mutation and a de novo NPHS1 mutation. Among 32 patients with two NPHS2 mutations who underwent kidney transplantation, only one developed late recurrence of focal segmental glomerulosclerosis (FSGS). Among 25 patients with sporadic SRNS and post-transplantation recurrence, we detected a heterozygous NPHS2 mutation in one case, and heterozygous variants/polymorphisms in 3 cases. Patients with two pathogenic NPHS2 mutations present with early-onset SRNS and very low incidence of post-transplantation recurrence. Heterozygous NPHS2 variants may play a role in atypical cases with mild, late-onset course, and recurrence after transplantation.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Open Access Maced J Med Sci
                Journal ID (iso-abbrev): Open Access Maced J Med Sci
                Title: Open Access Macedonian Journal of Medical Sciences
                Publisher: Republic of Macedonia (ID Design 2012/DOOEL Skopje )
                ISSN (Electronic): 1857-9655
                Publication date Collection: 15 October 2019
                Publication date (Electronic): 09 October 2019
                Volume: 7
                Issue: 19
                Pages: 3145-3148
                Affiliations
                [1 ]Biological Anthropology Department, Medical Research Division, National Research Centre, Cairo, Egypt
                [2 ]Biochemistry- Faculty of Pharmacy (Girls), Al–Azhar University, Cairo, Egypt
                [3 ]Department of Pediatrics (Nephrology Unit), Faculty of Medicine (for Girls), Al–Azhar University, Cairo, Egypt
                [4 ]Pediatric Nephrology Unite, Al–Hussein University Hospital, Cairo, Egypt
                [5 ]Slagelse Hospital, Internal Medicine Department, Slagelse, Denmark
                [6 ]Medical Molecular Genetics, National Research Center, Cairo, Egypt
                Author notes
                [* ] Correspondence: Moushira Zaki. Biological Anthropology Department, Medical Research Division, National Research Centre, Cairo, Egypt. E-mail: moushiraz@ 123456yahoo.com
                Article
                Publisher ID: OAMJMS-7-3145
                DOI: 10.3889/oamjms.2019.700
                PMC ID: 6953933
                SO-VID: 78e15bff-1cd0-4aab-8255-18e5e0074d3f
                Copyright © Copyright: © 2019 Moushira Zaki, Shreen El-Shaer, Sahar Rady, Manal Abd El-Salam, Ragaa Abd-El-Salam, Ibrahim Abdelfattah Alkashlan, Mohamed Saber, Sanaa Mohamed, Mohamed Hassaan, Eman Rabie, Khalda Amr.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0)

                History
                Date received : 16 May 2019
                Date revision received : 15 September 2019
                Date accepted : 16 September 2019
                Categories
                Subject: Basic Science

                Keywords: nphs2 mutation,steroid resistant nephrotic syndrome,r229q polymorphism
                Data availability:
                Keywords: nphs2 mutation, steroid resistant nephrotic syndrome, r229q polymorphism

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