OBJECTIVECongenital nephrotic syndrome (CNS) is defined as heavy proteinuria or nephrotic syndrome occurring before 3 months of age. It is characterized by early onset, resistance to steroid therapy and progressing to end-stage renal disease (ESRD). In recent years, several genes associated with CNS have been identified, such as NPHS1, NPHS2 and WT1. The mutations of these genes have been identified in the patients with CNS in Finland, other European countries, North Africa, North America, and Asia, respectively. However, the investigation of the above genes has not been performed in Chinese CNS patients. In this study, NPHS1 mutations in a Chinese family with CNS were detected and analyzed.

METHODSThere were two CNS patients in the investigated family. The proband, a 45-day-old boy, was born at fullterm and weighed 2700 g at birth. The placenta weighed 450 g. At the age of 10 days, generalized edema, proteinuria, hypoproteinemia, and hypoalbuminemia were found without renal insufficiency. The proband's sister, with the same phenotype and normal renal function, underwent renal biopsy at 5 years of age. Their parents and elder half-sister all had normal phenotypes. Genomic DNA samples were extracted from peripheral bloods of the proband, his family members and 50 unrelated, normal individuals. All 29 exons and exon-intron boundaries of NPHS1 were detected in the proband by polymerase chain reaction (PCR), direct DNA sequencing, and restriction enzyme analysis.

RESULTSThree heterozygous mutations of NPHS1, namely, G928A (D310N), 1893-1900del 8 (CGAAACCG), and G2869C (V957L) were identified in the proband. These mutations involved exons 8, 14, and 21. The same genotype was found in the proband's sister who had the same phenotype, but was not detected in proband's elder half-sister who had normal phenotype. Fifty normal individuals had no these mutations. The proband's mother with normal urinalysis had G928A (D310N) heterozygous mutation, and the father with normal urinalysis had two heterozygous mutations of 1893-1900del 8 (CGAAACCG) and G2869C (V957L). At the same time, three types of single nucleotide polymorphisms (SNPs), E117K (rs3814995), S1105S (rs2071327), and IVS27+45c > t, were confirmed in the proband. Another variant, IVS8+68 a > g had also been found.

CONCLUSIONThis is the first report about NPHS1 mutations in Chinese CNS kindred. These three heterozygous mutations of NPHS1 are novel genetic defects of CNS, which have not been described before.