气候变化领域集成服务门户(CCPortal): Gain-of-function factor H–related 5 protein impairs glomerular complement regulation resulting in kidney damage

CCPortal

DOI	10.1073/pnas.2022722118
	Gain-of-function factor H–related 5 protein impairs glomerular complement regulation resulting in kidney damage
	Malik T.H.; Gitterman D.P.; Lavin D.P.; Lomax-Browne H.J.; Hiemeyer E.C.; Moran L.B.; Boroviak K.; Cook H.T.; Gilmore A.C.; Mandwie M.; Ahmad A.; Alexander I.E.; Logan G.J.; Marchbank K.J.; Bradley A.; Pickering M.C.
发表日期	2021
ISSN	00278424
卷号	118 期号:13
英文摘要	Genetic variation within the factor H–related (FHR) genes is associated with the complement-mediated kidney disease, C3 glomerulopathy (C3G). There is no definitive treatment for C3G, and a significant proportion of patients develop end-stage renal disease. The prototypical example is CFHR5 nephropathy, through which an internal duplication within a single CFHR5 gene generates a mutant FHR5 protein (FHR5mut) that leads to accumulation of complement C3 within glomeruli. To elucidate how abnormal FHR proteins cause C3G, we modeled CFHR5 nephropathy in mice. Animals lacking the murine factor H (FH) and FHR proteins, but coexpressing human FH and FHR5mut (hFH-FHR5mut), developed glomerular C3 deposition, whereas mice coexpressing human FH with the normal FHR5 protein (hFH-FHR5) did not. Like in patients, the FHR5mut had a dominant gain-of-function effect, and when administered in hFH-FHR5 mice, it triggered C3 deposition. Importantly, adeno-associated virus vector-delivered homodimeric mini-FH, a molecule with superior surface C3 binding compared to FH, reduced glomerular C3 deposition in the presence of the FHR5mut. Our data demonstrate that FHR5mut causes C3G by disrupting the homeostatic regulation of complement within the kidney and is directly pathogenic in C3G. These results support the use of FH-derived molecules with enhanced C3 binding for treating C3G associated with abnormal FHR proteins. They also suggest that targeting FHR5 represents a way to treat complement-mediated kidney injury. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Complement; Immunology; Kidney
语种	英语
scopus关键词	adeno associated virus vector; complement component C3; complement factor H; adult; animal cell; animal experiment; animal tissue; Article; CFHR5 gene; controlled study; female; gain of function mutation; gene; gene control; genetic association; glomerulopathy; homeostasis; kidney disease; male; molecular pathology; mouse; nonhuman; priority journal; protein binding; protein degradation; protein expression; protein function; protein metabolism
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180064
作者单位	Centre for Inflammatory Disease, Imperial College London, London, W12 0NN, United Kingdom; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom; North West London Pathology, Imperial College Healthcare National Health Service Trust, London, W6 8RF, United Kingdom; Gene Therapy Research Unit, Children’s Medical Research Institute, Sydney Children’s Hospitals Network, The University of Sydney, Westmead, NSW 2145, Australia; Discipline of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, Australia; Translational and Clinical Research Institute, The Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, United Kingdom; National Renal Complement Therapeutics Centre, Newcastle-upon-Tyne, NE1 4LP, United Kingdom
推荐引用方式 GB/T 7714	Malik T.H.,Gitterman D.P.,Lavin D.P.,等. Gain-of-function factor H–related 5 protein impairs glomerular complement regulation resulting in kidney damage[J],2021,118(13).
APA	Malik T.H..,Gitterman D.P..,Lavin D.P..,Lomax-Browne H.J..,Hiemeyer E.C..,...&Pickering M.C..(2021).Gain-of-function factor H–related 5 protein impairs glomerular complement regulation resulting in kidney damage.Proceedings of the National Academy of Sciences of the United States of America,118(13).
MLA	Malik T.H.,et al."Gain-of-function factor H–related 5 protein impairs glomerular complement regulation resulting in kidney damage".Proceedings of the National Academy of Sciences of the United States of America 118.13(2021).