A high-impact FN1 variant correlates with fibronectin-mediated glomerulopathy via decreased binding to collagen type IV

作者全名："Qiu, Jiawen; Chi, Huan; Gan, Chun; Zhou, Xindi; Chen, Dan; Yang, Qing; Chen, Yaxi; Wang, Mo; Yang, Haiping; Jiang, Wei; LI, Qiu"

作者地址："[Qiu, Jiawen; Chi, Huan; Gan, Chun; Zhou, Xindi; Chen, Dan; Yang, Qing; Wang, Mo; Yang, Haiping; Jiang, Wei; LI, Qiu] Chongqing Med Univ, Chongqing Key Lab Pediat, China Int Sci & Technol Cooperat Base Child Dev &, Pediat Res Inst,Dept Nephrol,Minist Educ,Natl Clin, Chongqing, Peoples R China; [Chen, Yaxi] Chongqing Med Univ, Affiliated Hosp 2, Ctr Lipid Res, Chongqing, Peoples R China; [Chen, Yaxi] Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Key Lab Mol Biol Infect Dis,Minist Educ,Dept Infec, Chongqing, Peoples R China"

通信作者："Jiang, W; Li, Q (通讯作者)，Chongqing Med Univ, Chongqing Key Lab Pediat, China Int Sci & Technol Cooperat Base Child Dev &, Pediat Res Inst,Dept Nephrol,Minist Educ,Natl Clin, Chongqing, Peoples R China."

来源：PATHOLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001001511100001

JCR分区：Q1

影响因子：3.6

年份：2023

卷号：55

期号：4

开始页：498

结束页：507

文献类型：Article

关键词：Glomerular basement membrane; fibronectin variant; thin base-ment membrane nephropathy; 4; 5

摘要："The glomerular basement membrane (GBM) consists of laminins, collagen IV, nidogens, and fibronectin and is essential for filtration barrier integrity in the kidney. Critically, structural and functional abnormalities in the GBM are involved in chronic kidney disease (CKD) occurrence and development. Fibronectin is encoded by FN1 and is essential for podocyte-podocyte and podocyte-matrix in-teractions. However, disrupted or disordered fibronectin occurs in many kidney diseases. In this study, we identified a novel mutation (c.3415G>A) in FN1 that causes glomerular fibronectin-specific deposition in a gain-of-function manner, that may be associated with thin basement membrane ne-phropathy (TBMN) and expand the spectrum of phenotypes seen in glomerulopathy with fibronectin deposits (GFND). Our studies confirmed this variant increased fibronectin's ability to bind to integrin, thereby maintaining podocyte adhesion. Also, we hypothesised that TBMN arose as the fibronectin variant exhibited a decreased capacity to bind COL4A3/4. Our study is the first to identify and link this novel pathogenic mutation (c.3415G>A) in FN1 to GFND as well as TBMN, which may broaden the phenotype and mutation spectrums of the FN1 gene. We believe our data will posi-tively impact genetic counselling and prenatal diagnostics for GFND with TBMN and other associated conditions that may be commonly benign conditions in humans, and may not require proteinuria-lowering treatments or renal biopsy."

基金机构："Multi-Center Innovation Platform for Early Development and Major Diseases of Perinatal Newborns in Different Altitude Areas; Second Batch of Funds for Chongqing Talents and Famous Teachers [020210]; General Project of Basic Research of Key Laboratory of Ministry of Education for Research on Child Developmental Diseases, Children's Hospital of Chongqing Medical University, China [GBRP-202111]; National Natural Science Foundation of China [81970618, 82200906]"

基金资助正文："This study was supported by grants from Multi-Center Innovation Platform for Early Development and Major Diseases of Perinatal Newborns in Different Altitude Areas (Special Funds for The Central Government to Guide Local Scientific and Technological Development) , the Second Batch of Funds for Chongqing Talents and Famous Teachers (No. 020210) , General Project of Basic Research of Key Laboratory of Ministry of Education for Research on Child Developmental Diseases, Children's Hospital of Chongqing Medical University, China (No. GBRP-202111) and the National Natural Science Foundation of China (No. 81970618 and No. 82200906) . The authors state that there are no conflicts of interest to disclose."