Nphs1 gene mutations confirm congenital nephrotic syndrome in four Brazilian cases: a novel mutation is described

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOAutosomal 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 NPHS1 gene distributed among all nephrin domains. The main objective of this study was to perform the analysis of NPHS1 gene in patients with congenital nephrotic syndrome in order to determine the molecular cause of the disease. We performed direct sequencing of NPHS1 gene in four children. 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. 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 South Eastern region of Brazil, although the analysis of a larger sample is required to obtain more indicative epidemiological data.Autosomal recessive mutations inNPHS1geneareacommoncauseofcongenital nephrotic syndrome (CNS). The disorder is characterized by massiveproteinuria that manifestsin uteroor in the neonatal period during thefirst3months of life.NPHS1encodes nephrin, a member of the immunoglobulin fam-ily of cell adhesion molecules and the main protein expressed at the renal slitdiaphragm. Currently, there are approximately 250 mutations described in theNPHS1gene distributed among all nephrin domains. The main objective of thisstudy was to perform the analysis of theNPHS1gene in patients with congenitalnephrotic syndrome in order to determine the molecular cause of the disease.Methods:Direct sequencing ofNPHS1gene in four children was performed.Results:Each patient was heterozygous for twopathogenic mutations disclosingthemolecularcauseofthediseasein100%ofthecases.Weidentified six differ-ent mutations, consisting of one in-framedeletion, one frameshift, and four mis-sense substitutions. The p.Val736Met mutation that is described here for thefirsttime was considered pathogenic by different mutation predictive algorithms.Regardless of the type of mutation, three patients had a bad outcome and diedConclusions:Despite the small size of the cohort, this study contributed to theincreasing number of deleterious mutations in theNPHS1gene by describing anew mutation. Also, since we identifiedNPHS1pathogenic mutations as thecause of the disease in all cases analyzed, it might be a frequent cause of CNSin the South Eastern region of Brazil, although the analysis of a larger sampleis required to obtain more indicative epidemiological data219753757FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO2012/51109-0478444/08-7; 141072/201