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

Ling Zhuo,Guisen Li,Lulin Huang,Li Wang,Zhenglin Yang

doi:10.1186/s12881-019-0845-4

Ling Zhuo, Guisen Li + Show 3 more

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https://doi.org/10.1186/s12881-019-0845-4

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Abstract

BackgroundFocal 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.MethodsA 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.ResultsThirty-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.ConclusionsNPHS1 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.

Highlights

Focal segmental glomerulosclerosis (FSGS) is still one of the common causes of refractory nephrotic syndrome
The variant distributions of NPHS1 in FSGS patients Twenty-two variants of NPHS1 gene were identified in 309 FSGS patients, including 12 synonymous mutations, and 17 missense mutations
NPHS1 was first demonstrated to be the causal gene for congenital nephrotic syndrome of Finnish type [20], subsequent studies have confirmed that it was a causative gene or susceptibility gene for a variety of kidney diseases, such as steroid-resistant nephrotic syndrome (SRNS), FSGS, minimal change disease with nephrotic syndrome (MCNS), IgA nephropathy, et al [9, 11, 12, 21,22,23,24]

Summary

Introduction

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. We investigated the specific mutations of NPHS1 gene in Chinese patients with sporadic FSGS. Focal segmental glomerulosclerosis (FSGS) is a syndrome with unique clinical and pathological manifestations. New medications continue to emerge, FSGS is still one of the most common causes which contributes to refractory nephrotic syndrome [1,2,3]. About 8–14% of patients with FSGS could be explained by podocyte-related gene mutations. NPHS1, that relates to congenital nephrotic syndrome (CNS) and SRNS, is one of the most frequently reported genes. The mutations of NPHS1 gene could lead to the occurrence of different degrees of kidney diseases, studies which investigated the relationship between NPHS1 gene mutations and FSGS were limited, especially in China [8, 11,12,13]

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