NPHS2 mutations account for only 15% of nephrotic syndrome cases

Abstract

Background: Nephrotic syndrome is traditionally classified on the basis of the response to standard steroid treatment. Mutations in more than 24 genes have been associated with nephrotic syndrome in children, although the great majority of steroid-resistant cases have been attributed to mutations in three main genes: NPHS1, NPHS2 and WT1. The aims of this study were to identify mutations in these genes more frequently reported as mutated and to characterize each variation using different in silico prediction algorithms in order to understand their biological functions. Methods: We performed direct sequence analysis of exons 8 and 9 of WT1, 8 exons of NPHS2 and 29 exons of NPHS1, including NPHS2 and NPHS1 intron-exon boundary sequences, as well as 700bp of the 5 UTR from both genes in 27 steroid-resistant patients aged between 3months and 18years. Results: Analysis of the NPHS2 gene revealed four missense mutations, one frameshift mutation and three variations in the 5 UTR. Four patients presented compound heterozygosis, and four other patients presented one heterozygous alteration only. WT1 and NPHS1 gene analysis did not reveal any mutations. Discussion: This is the first study focusing on genetics ofSRNS in Brazilian children. Identification of mutations is important because it couldinfluence physicians' decision on patient treatment, as patients carrying mutations canbe spared the side effects of immunosuppressive therapy and ultimately could beconsidered for kidney transplantation from a living donor. Conclusions: After molecular analysis of the genes more frequently reported as mutated in 27 steroid-resistant nephrotic syndrome patients, we identified NPHS2 mutations confirming the hereditary character of the kidney disease in only 14.8% of patients. Therefore, the next step is to perform a next generation sequencing based analysis of glomeluropathy-related panel of genes for the remaining patients in order to search for mutations in other genes related to steroid-resistant nephrotic syndrome.