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      NPHS2 Mutations: A Closer Look to Latin American Countries

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          Abstract

          Nephrotic syndrome is one of the most common kidney pathologies in childhood, being characterized by proteinuria, edema, and hypoalbuminemia. In clinical practice, it is divided into two categories based on the response to steroid therapy: steroid-sensitive and steroid resistant. Inherited impairments of proteins located in the glomerular filtration barrier have been identified as important causes of nephrotic syndrome, with one of these being podocin, coded by NPHS2 gene. NPHS2 mutations are the most frequent genetic cause of steroid resistant nephrotic syndrome. The aim of this review is to update the list of NPHS2 mutations reported between June 2013 and February 2017, with a closer look to mutations occurring in Latin American countries.

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          Human non-synonymous SNPs: server and survey.

          V. Ramensky (2002)
          Human single nucleotide polymorphisms (SNPs) represent the most frequent type of human population DNA variation. One of the main goals of SNP research is to understand the genetics of the human phenotype variation and especially the genetic basis of human complex diseases. Non-synonymous coding SNPs (nsSNPs) comprise a group of SNPs that, together with SNPs in regulatory regions, are believed to have the highest impact on phenotype. Here we present a World Wide Web server to predict the effect of an nsSNP on protein structure and function. The prediction method enabled analysis of the publicly available SNP database HGVbase, which gave rise to a dataset of nsSNPs with predicted functionality. The dataset was further used to compare the effect of various structural and functional characteristics of amino acid substitutions responsible for phenotypic display of nsSNPs. We also studied the dependence of selective pressure on the structural and functional properties of proteins. We found that in our dataset the selection pressure against deleterious SNPs depends on the molecular function of the protein, although it is insensitive to several other protein features considered. The strongest selective pressure was detected for proteins involved in transcription regulation.
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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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              Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2).

              Martin Zenker, Rasheed Gbadegesin, Friedhelm Hildebrandt … (2007)
              Mutations in each of the NPHS1, NPHS2, WT1, and LAMB2 genes have been implicated in nephrotic syndrome, manifesting in the first year of life. The relative frequency of causative mutations in these genes in children with nephrotic syndrome manifesting in the first year of life is unknown. Therefore, we analyzed all 4 of the genes jointly in a large European cohort of 89 children from 80 families with nephrotic syndrome manifesting in the first year of life and characterized genotype/phenotype correlations. We performed direct exon sequencing of NPHS1, NPHS2, and the relevant exons 8 and 9 of WT1, whereas the LAMB2 gene was screened by enzymatic mismatches cleavage. We detected disease-causing mutations in 66.3% (53 of 80) families (NPHS1, NPHS2, WT1, and LAMB2: 22.5%, 37.5%, 3.8%, and 2.5%, respectively). As many as 84.8% of families with congenital onset (0-3 months) and 44.1% with infantile onset (4-12 months) of nephrotic syndrome were explained by mutations. NPHS2 mutations were the most frequent cause of nephrotic syndrome among both families with congenital nephrotic syndrome (39.1%) and infantile nephrotic syndrome (35.3%), whereas NPHS1 mutations were solely found in patients with congenital onset. Of 45 children in whom steroid treatment was attempted, only 1 patient achieved a lasting response. Of these 45 treated children, 28 had causative mutations, and none of the 28 responded to treatment. First, two thirds of nephrotic syndrome manifesting in the first year of life can be explained by mutations in 4 genes only (NPHS1, NPHS2, WT1, or LAMB2). Second, NPHS1 mutations occur in congenital nephrotic syndrome only. Third, infants with causative mutations in any of the 4 genes do not respond to steroid treatment; therefore, unnecessary treatment attempts can be avoided. Fourth, there are most likely additional unknown genes mutated in early-onset nephrotic syndrome.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Biomed Res Int
                Journal ID (iso-abbrev): Biomed Res Int
                Journal ID (publisher-id): BMRI
                Title: BioMed Research International
                Publisher: Hindawi
                ISSN (Print): 2314-6133
                ISSN (Electronic): 2314-6141
                Publication date (Print): 2017
                Publication date (Electronic): 12 July 2017
                Volume: 2017
                Electronic Location Identifier: 7518789
                Affiliations
                1Center for Molecular Biology and Genetic Engineering (CBMEG), State University of Campinas (UNICAMP), Campinas, SP, Brazil
                2Integrated Center of Pediatric Nephrology (CIN), Department of Pediatrics, School of Medical Sciences (FCM), State University of Campinas (UNICAMP), Campinas, SP, Brazil
                3Department of Medical Genetics, School of Medical Sciences (FCM), Interdisciplinary Group for the Study of Sex Determination and Differentiation (GIEDDS), School of Medical Sciences (FCM), State University of Campinas (UNICAMP), Campinas, SP, Brazil
                4Interdisciplinary Group for the Study of Sex Determination and Differentiation (GIEDDS), Pediatrics Endocrinology, Department of Pediatrics, School of Medical Sciences (FCM), State University of Campinas, UNICAMP, Campinas, SP, Brazil
                Author notes
                *Mara Sanches Guaragna: mara.guaragna@ 123456gmail.com

                Academic Editor: Andreas Kronbichler

                Author information
                http://orcid.org/0000-0002-6508-8571
                http://orcid.org/0000-0002-2991-7678
                http://orcid.org/0000-0003-0521-9100
                Article
                DOI: 10.1155/2017/7518789
                PMC ID: 5529630
                SO-VID: 0f82d2d6-ae99-4407-a102-198346a5a3e6
                Copyright © Copyright © 2017 Mara Sanches Guaragna et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 3 March 2017
                Date revision received : 2 June 2017
                Date accepted : 8 June 2017
                Funding
                Funded by: Fundação de Amparo à Pesquisa do Estado de São Paulo
                Award ID: 2012/51109-9
                Award ID: 2012/51109-0
                Award ID: 2013/24088-4
                Funded by: Conselho Nacional de Desenvolvimento Científico e Tecnológico
                Award ID: 478444/08-7
                Award ID: 141072/2010
                Categories
                Subject: Review Article

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