Mara S Guaragna1, Thaís Lira Cleto2, Marcela Lopes Souza1, Anna Cristina G B Lutaif3, Luiz Cláudio Gonçalves de Castro4, Maria Goretti Moreira Guimarães Penido5, Andréa T Maciel-Guerra6, Vera M S Belangero3, Gil Guerra-Junior7,8,9, Maricilda P De Mello1. 1. Center for Molecular Biology and Genetic Engineering, University of Campinas, Sao Paulo, Brazil. 2. Nephrology Center of University Hospital Pedro Ernesto, Rio de Janeiro, Brazil. 3. Pediatric Nephrology, Department of Pediatrics, School of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil. 4. Pediatric Endocrinology, Faculty of Medicine, University of Brasilia, Brasilia, Federal District, Brazil. 5. Pediatric Department, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. 6. Department of Medical Genetics, School of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil. 7. Interdisciplinary study group of determination and sex differentiation, School of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil. 8. Pediatric Research Center, School of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil. 9. Pediatric Endocrinology, Pediatric Department, School of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil.
Abstract
AIM: Autosomal recessive mutations in NPHS1 gene are a common cause of congenital nephrotic syndrome (CNS). The disorder is characterized by massive proteinuria that manifests in utero or in the neonatal period during the first 3 months of life. NPHS1 encodes nephrin, a member of the immunoglobulin family of cell adhesion molecules and the main protein expressed at the renal slit diaphragm. Currently, there are approximately 250 mutations described in the NPHS1 gene distributed among all nephrin domains. The main objective of this study was to perform the analysis of the NPHS1 gene in patients with congenital nephrotic syndrome in order to determine the molecular cause of the disease. METHODS: Direct sequencing of NPHS1 gene in four children was performed. RESULTS: Each patient was heterozygous for two pathogenic mutations disclosing the molecular cause of the disease in 100% of the cases. We identified six different mutations, consisting of one in-frame deletion, one frameshift, and four missense substitutions. The p.Val736Met mutation that is described here for the first time was considered pathogenic by different mutation predictive algorithms. Regardless of the type of mutation, three patients had a bad outcome and died CONCLUSIONS: Despite the small size of the cohort, this study contributed to the increasing number of deleterious mutations in the NPHS1 gene by describing a new mutation. Also, since we identified NPHS1 pathogenic mutations as the cause of the disease in all cases analyzed, it might be a frequent cause of CNS in the South Eastern region of Brazil, although the analysis of a larger sample is required to obtain more indicative epidemiological data.
AIM: Autosomal recessive mutations in NPHS1 gene are a common cause of congenital nephrotic syndrome (CNS). The disorder is characterized by massive proteinuria that manifests in utero or in the neonatal period during the first 3 months of life. NPHS1 encodes nephrin, a member of the immunoglobulin family of cell adhesion molecules and the main protein expressed at the renal slit diaphragm. Currently, there are approximately 250 mutations described in the NPHS1 gene distributed among all nephrin domains. The main objective of this study was to perform the analysis of the NPHS1 gene in patients with congenital nephrotic syndrome in order to determine the molecular cause of the disease. METHODS: Direct sequencing of NPHS1 gene in four children was performed. RESULTS: Each patient was heterozygous for two pathogenic mutations disclosing the molecular cause of the disease in 100% of the cases. We identified six different mutations, consisting of one in-frame deletion, one frameshift, and four missense substitutions. The p.Val736Met mutation that is described here for the first time was considered pathogenic by different mutation predictive algorithms. Regardless of the type of mutation, three patients had a bad outcome and died CONCLUSIONS: Despite the small size of the cohort, this study contributed to the increasing number of deleterious mutations in the NPHS1 gene by describing a new mutation. Also, since we identified NPHS1 pathogenic mutations as the cause of the disease in all cases analyzed, it might be a frequent cause of CNS in the South Eastern region of Brazil, although the analysis of a larger sample is required to obtain more indicative epidemiological data.
Authors: Mara Sanches Guaragna; Anna Cristina Gervásio de Brito Lutaif; Marcela Lopes de Souza; Andréa Trevas Maciel-Guerra; Vera Maria Santoro Belangero; Gil Guerra-Júnior; Maricilda Palandi de Mello Journal: Mol Genet Genomics Date: 2019-09-13 Impact factor: 3.291
Authors: Annika Möller-Kerutt; Juan E Rodriguez-Gatica; Karin Wacker; Rohan Bhatia; Jan-Peter Siebrasse; Nanda Boon; Veerle Van Marck; Peter Boor; Ulrich Kubitscheck; Jan Wijnholds; Hermann Pavenstädt; Thomas Weide Journal: J Am Soc Nephrol Date: 2021-03-09 Impact factor: 10.121
Authors: C James Cooper; Nikkita T Dutta; Claire E Martin; Tino D Piscione; Paul S Thorner; Nina Jones Journal: PLoS One Date: 2018-09-13 Impact factor: 3.240
Authors: Luciana S Feltran; Andreia Watanabe; Mara S Guaragna; Ivan C Machado; Fernanda M S Casimiro; Precil D M M Neves; Lilian M Palma; Patrícia Varela; Maria H Vaisbich; Suely K N Marie; Inalda Facincani; João B Pesquero; Vera M S Belangero; Matthew G Sampson; Paulo C Koch Nogueira; Luiz F Onuchic Journal: Kidney Int Rep Date: 2019-11-21