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      NPHS2 V260E Is a Frequent Cause of Steroid-Resistant Nephrotic Syndrome in Black South African Children

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          In South Africa (SA), steroid-resistant nephrotic syndrome (SRNS) is more frequent in black than in Indian children.


          Seeking a genetic basis for this disparity, we enrolled 33 Indian and 31 black children with steroid-sensitive nephrotic syndrome (SSNS) and SRNS from KwaZulu-Natal, SA; SRNS children underwent kidney biopsy. We sequenced NPHS2 and genotyped APOL1 in 15 SSNS and 64 SRNS unrelated patients and 104 controls and replicated results in 18 black patients with steroid-resistant focal segmental glomerulosclerosis (SR-FSGS). Known FSGS genes (n = 21) were sequenced in a subset of patients.


          Homozygosity for NPHS2 V260E was found in 8 of 30 black children with SRNS (27%); all 260E/E carriers had SR-FSGS. Combining SR-FSGS patients from the 2 groups, 14 of 42 (33%) were homozygous for V260E. One black control was heterozygous for V260E; no Indian patients or controls were carriers. Haplotype analysis indicated that homozygosity for V260E was not explained by cryptic consanguinity. Children with NPHS2 260E/E developed SRNS at earlier age than noncarriers (34 vs. 78 months, P = 0.01), and none achieved partial or complete remission (0% vs. 47%, P = 0.002). APOL1 variants did not associate with NS. Sequencing FSGS genes identified a CD2AP predicted pathogenic variant in the heterozygous state in 1 Indian case with SR-FSGS.


          NPHS2 260E/E was present in one-third of black FSGS patients, was absent in black controls and Indian patients, and affected patients were unresponsive to therapy. Genotyping V260E in black children from South Africa with NS will identify a substantial group with SR-FSGS, potentially sparing these children biopsy and ineffective steroid treatment.

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          Most cited references 31

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

          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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            Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry cohort.

            Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome.
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              Management of childhood onset nephrotic syndrome.

              The therapeutic approach to childhood nephrotic syndrome is based on a series of studies that began with an international collaborative effort sponsored by the International Study of Kidney Disease in Children in 1967. The characteristics of children presenting with nephrotic syndrome have changed over recent decades with greater frequency of the challenging condition focal segmental glomerulosclerosis and a greater prevalence of obesity and diabetes mellitus, which may be resistant to glucocorticoids in the former and exacerbated by long-term glucocorticoid therapy in the latter 2 conditions. The Children's Nephrotic Syndrome Consensus Conference was formed to systematically review the published literature and generate a children's primary nephrotic syndrome guideline for use in educational, therapeutic, and research venues.

                Author and article information

                Kidney Int Rep
                Kidney Int Rep
                Kidney International Reports
                29 July 2018
                November 2018
                29 July 2018
                : 3
                : 6
                : 1354-1362
                [1 ]University of KwaZulu-Natal, Durban, South Africa
                [2 ]Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
                [3 ]School of Public Health, University of Witwatersrand, Johannesburg, South Africa
                [4 ]Department of Pediatrics-Nephrology; University of Michigan School of Medicine, Ann Arbor, Michigan, USA
                [5 ]Advanced Biomedical Computing Center, Frederick National Laboratory, Frederick, Maryland, USA
                [6 ]Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, USA
                [7 ]Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
                Author notes
                [] Correspondence: Cheryl A. Winkler, 8560 Progress Drive, National Cancer Institute, Frederick National Laboratory, Frederick, Maryland 21701, USA. winklerc@
                © 2018 International Society of Nephrology. Published by Elsevier Inc.

                This is an open access article under the CC BY-NC-ND license (

                Clinical Research

                steroid resistance, apol1, cd2ap, fsgs, nephrotic syndrome, nphs2


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