A comprehensive analysis of NPHS1 gene mutations in patients with sporadic focal segmental glomerulosclerosis

Abstract

Background Focal segmental glomerulosclerosis (FSGS) is still one of the common causes of refractory nephrotic syndrome. Nephrin, encoded by podocyte-specific NPHS1 gene, participated in the pathogenesis of FSGS. The sites of NPHS1 mutations in FSGS is not clarified very well. In this study, we investigated the specific mutations of NPHS1 gene in Chinese patients with sporadic FSGS. Methods A total of 309 patients with sporadic FSGS were collected and screened for NPHS1 mutations by second-generation sequencing. The variants were compared with those extracted from 2504 healthy controls in the 1000 Genomes Project. The possible pathogenic roles of missense variants were predicted by three different software. We also compared these candidate causal mutations with those summarized from the previous studies. Results Thirty-two genetic mutations of NPHS1 gene were identified in FSGS patients, including 12 synonymous mutations, 17 missense mutations, 1 splicing mutation, and 2 intron mutations, of which c.G3315A (p.S1105S) was the most common variant (261/309). A novel missense mutation c.G2638 T (p.V880F) and a novel splicing mutation 35830957 C > T were identified in FSGS patients. The frequencies of the four synonymous mutations (c.C294T [p.I98I], c.C2223T [p.T741 T], c.C2289T [p.V763 V], c.G3315A [p.S1105S]) were much higher in FSGS patients than in controls. The frequencies of the four missense mutations (c.G349A [p.E117K], c.G1339A [p.E447K], c.G1802C [p.G601A], c.C2398T [p.R800C]) were much higher and one (c.A3230G [p.N1077S]) was lower in FSGS patients than in controls. Five missense mutations, c.C616A (p.P206T), c.G1802C (p.G601A), c.C2309T (p.P770L), c.G2869C (p.V957 L), and c.C3274T (p.R1092C), were predicted to be pathogenic mutations by software analysis. Conclusions NPHS1 gene mutations were quite common in sporadic FSGS patients. We strongly recommend mutation analysis of the NPHS1 gene in the clinical management of FSGS patients.

Anatomical structures, cell types and biomarkers of the Human Reference Atlas

“…For example, the gene NPHS1, which encodes nephrin, is one of the top markers of healthy podocytes and is essential for glomerular function. Mutations in NPHS1 may be found in patients with proteinuria 158 . The kidney ASCT+B table records that the gene biomarker NPHS1 (Fig.…”

MAGI-2 orchestrates the localization of backbone proteins in the slit diaphragm of podocytes

“…5,[8][9][10] Many genetic analyses have also revealed the importance of these gene mutations in the development of nephrotic syndrome in humans. [11][12][13][14][15][16][17][18][19][20] Thus, we were compelled to elucidate how these backbone proteins are physiologically localized and preserved in podocytes. Actually, scaffold proteins such as podocin, CD2-associated protein (CD2AP), and Zonula occludens-1 (ZO-1) are reported to be involved in stabilizing these backbone proteins.…”

Anti-apoptosis mechanism of triptolide based on network pharmacology in focal segmental glomerulosclerosis rats

“…The clinical manifestations of FSGS patients are massive proteinuria, hematuria, hypertension, and progressive decrease in renal function. The condition of 3.6% of patients with end-stage renal disease developed from FSGS [1,2]. Currently, the main clinical therapies for FSGS are immunologic drugs, glucocorticoids, and blockers of the renin-angiotensin system; however, their therapeutic effects are not satisfactory.…”