Identification of a Novel ACTN4 Gene Mutation Which Is Resistant to Primary Nephrotic Syndrome Therapy.

Lingzhang Meng,Mali Lin,Qingmei Lu,Yuming Huang,Junhua Tan,Dongming Li,Genliang Li,Ken Huang,Junli Wang,Qiuju Wei,Aibo Wei,Xulong Cai,Yonghua Liang ,Lijuan Yang ,Jie Wang ,Meirong Huang ,Sheng Cao ,Ning Lin ,Yunfei Guo ,Xiajing Chen ,Jing Zhao ,Yunguang Liu

doi:10.1155/2019/5949485

Abstract

ACTN4, a gene which codes for the protein α-actinin-4, is critical for the maintenance of the renal filtration barrier. It is well known that ACTN4 mutations can lead to kidney dysfunction, such as familial focal segmental glomerulosclerosis (FSGS), a common cause of primary nephrotic syndrome (PNS). To elucidate whether other mutations of ACTN4 exist in PNS patients, we sequenced the ACTN4 gene in biopsies collected from 155 young PNS patients (≤16 years old). The patients were classified into five groups: FSGS, minimal change nephropathy, IgA nephropathy, membranous nephropathy, and those without renal puncture. Ninety-eight healthy people served as controls. Samples were subjected to Illumina's next generation sequencing protocols using FastTarget target gene capture method. We identified 5 ACTN4 mutations which occurred only in PNS patients: c.1516G > A (p.G506S) on exon 13 identified in two PNS patients, one with minimal change nephropathy and another without renal puncture; c.1442 + 10G > A at the splice site in a minimal change nephropathy patient; c.2191-4G > A at the cleavage site, identified from two FSGS patients; and c.1649A > G (p.D550G) on exon 14 together with c.2191-4G > A at the cleavage sites, identified from two FSGS patients. Among these, c.1649A > G (p.D550G) is a novel ACTN4 mutation. Patients bearing the last two mutations exhibited resistance to clinical therapies.

Highlights

primary nephrotic syndrome (PNS) is a type of immune-mediated glomerular disease, resulting in a series of pathophysiological changes due to increased permeability of the glomerular filtration membranes, caused the loss of plasma proteins
Previous studies proved that ACTN4 mutations play an important role in the development of PNS [4, 11]
Detsika et al found that the abnormal expression of α-actinin-4 and glomerular-associated proteins was related to the pathogenesis of focal segmental glomerulosclerosis (FSGS) [12]

Summary

Introduction

PNS is a type of immune-mediated glomerular disease, resulting in a series of pathophysiological changes due to increased permeability of the glomerular filtration membranes, caused the loss of plasma proteins. PNS is usually classified into 5 classes based on clinical features: FSGS, minimal change. Α-actinin-4, a protein expressed widely throughout the body, but enriched in the kidney, is encoded by the ACTN4 gene. Several mutations of this gene have been found, and it usually correlates with abnormal serum levels and the function of α-actinin-4, especially in those patients suffering with FSGS [4]. We confirmed that ACTN4 mutations exist in FSGS patients and in patients with minimal change nephropathy and those without renal puncture. We discovered a new ACTN4 mutation, which could confer resistance to certain clinical therapies

Results

Discussion

Materials and Methods

Ethical Approval

Conflicts of Interest