Novel variants in CRB2 targeting the malfunction of slit diaphragm related to focal segmental glomerulosclerosis

作者全名："Yang, Qing; Tang, Dan; Gan, Chun; Bai, Mi; Song, Xiaomei; Jiang, Wei; Li, Qiu; Chen, Yaxi; Zhang, Aihua; Wang, Mo"

作者地址："[Yang, Qing; Gan, Chun; Song, Xiaomei; Jiang, Wei; Li, Qiu; Wang, Mo] Chongqing Med Univ, Dept Nephrol, Pediat Res Inst, Childrens Hosp,Natl Clin Res Ctr Child Hlth & Diso, Chongqing, Peoples R China; [Tang, Dan] Third Hosp Mianyang, Sichuan Mental Hlth Ctr, Dept Pediat, Mianyang 621000, Sichuan, Peoples R China; [Bai, Mi; Zhang, Aihua] Nanjing Med Univ, Childrens Hosp, Dept Nephrol, State Key Lab Reprod Med, 72 Guangzhou Rd, Nanjing 210008, Peoples R China; [Chen, Yaxi] Chongqing Med Univ, Ctr Lipid Res, Chongqing, Peoples R China; [Chen, Yaxi] Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect Dis,Key Lab Mol Biol Infect Dis,Minist, Chongqing, Peoples R China"

通信作者："Wang, M (通讯作者)，Chongqing Med Univ, Dept Nephrol, Pediat Res Inst, Childrens Hosp,Natl Clin Res Ctr Child Hlth & Diso, Chongqing, Peoples R China."

来源：PEDIATRIC NEPHROLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001030782100001

JCR分区：Q1

影响因子：2.6

年份：2023

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期号：　

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文献类型：Article; Early Access

关键词：CRB2; Mutation; SRNS; FSGS; Slit diaphragm-associated proteins

摘要："Background Focal segmental glomerulosclerosis (FSGS) is a leading cause of steroid-resistant nephrotic syndrome (SRNS) that predominantly affects the podocytes. While mutations in genes causing pediatric SRNS have enhanced our understanding of FSGS, the disease's etiology remains complex and poorly understood.Methods Whole exome sequencing (WES) was performed on a 9-year-old girl with SRNS associated with FSGS (SRNS-FSGS). We analyzed the expression of CRB2, slit diaphragm (SD)-associated proteins, and sphingosine 1-phosphate receptor 1 (S1PR1) in the proband and CRB2 knock-down podocytes.Results In this study, we identified two novel compound heterozygous mutations in the Crumbs homolog 2 (CRB2) gene (c.2905delinsGCCACCTCGCGCTGGCTG, p.T969Afs*179 and c.3268C > G, p.R1090G) in a family with early-onset SRNS-FSGS. Our findings demonstrate that these CRB2 abnormalities were the underlying cause of SRNS-FSGS. CRB2 defects led to the dysfunction of podocyte SD-related proteins, including podocin, nephrin, and zonula occludens-1 (ZO-1), by reducing the phosphorylation level of S1PR1. Interestingly, the podocytic cytoskeleton remained unaffected, as demonstrated by normal expression and localization of synaptopodin. Our study also revealed a secondary decrease in CRB2 expression in idiopathic FSGS patients, indicating that CRB2 mutations may cause FSGS through a previously unknown mechanism involving SD-related proteins.Conclusions Overall, our findings shed new light on the pathogenesis of SRNS-FSGS and revealed that the novel pathogenic mutations in CRB2 contribute to the development of FSGS through a previously unknown mechanism involving SD-related proteins."

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