A haplotype in CFH family genes confers high risk of rare glomerular nephropathies

Abstract Despite distinct renal lesions, a series of rare glomerular nephropathies are reportedly mediated by complement overactivation. Genetic variations in complement genes contribute to disease risk, but the relationship of genotype to phenotype has not been straightforward. Here, we screened 11...

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Autores principales: Yin Ding, Weiwei Zhao, Tao Zhang, Hao Qiang, Jianping Lu, Xin Su, Shuzhen Wen, Feng Xu, Mingchao Zhang, Haitao Zhang, Caihong Zeng, Zhihong Liu, Huimei Chen
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Publicado: Nature Portfolio 2017
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spelling oai:doaj.org-article:8b01a17b909c4a4fb5cba79f402d8a1c2021-12-02T16:08:19ZA haplotype in CFH family genes confers high risk of rare glomerular nephropathies10.1038/s41598-017-05173-82045-2322https://doaj.org/article/8b01a17b909c4a4fb5cba79f402d8a1c2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05173-8https://doaj.org/toc/2045-2322Abstract Despite distinct renal lesions, a series of rare glomerular nephropathies are reportedly mediated by complement overactivation. Genetic variations in complement genes contribute to disease risk, but the relationship of genotype to phenotype has not been straightforward. Here, we screened 11 complement genes from 91 patients with atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G) and membranoproliferative glomerulonephritis type I (MPGN I), and identified the concomitant presence of three missense variations located within the human complement Factor H (CFH) gene cluster. The three variations, rs55807605, rs61737525 and rs57960694, have strong linkage disequilibrium; subsequent haplotype analysis indicated that ATA increased the susceptibility of these renal diseases. In silico analysis, the CFHR3 rs61737525-T risk allele altered the physical and structural properties and generated a reduction in binding affinity of the CFHR3/C3b complex. Surface plasmon resonance (SPR) binding analysis further demonstrated the substitution induced a decrease of two orders of magnitude in C3b-binding properties, with a declined cofactor activity in fluid phase. These data suggest that the haplotype carrying the causative allele behaves as a partial C3 convertase deficiency, predisposing individuals to diverse pathologic lesions underlying complement overactivation. Such genotype-phenotype discrepancies allow better understanding about these nephropathies mediated by genetic complement disorders.Yin DingWeiwei ZhaoTao ZhangHao QiangJianping LuXin SuShuzhen WenFeng XuMingchao ZhangHaitao ZhangCaihong ZengZhihong LiuHuimei ChenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Yin Ding
Weiwei Zhao
Tao Zhang
Hao Qiang
Jianping Lu
Xin Su
Shuzhen Wen
Feng Xu
Mingchao Zhang
Haitao Zhang
Caihong Zeng
Zhihong Liu
Huimei Chen
A haplotype in CFH family genes confers high risk of rare glomerular nephropathies
description Abstract Despite distinct renal lesions, a series of rare glomerular nephropathies are reportedly mediated by complement overactivation. Genetic variations in complement genes contribute to disease risk, but the relationship of genotype to phenotype has not been straightforward. Here, we screened 11 complement genes from 91 patients with atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G) and membranoproliferative glomerulonephritis type I (MPGN I), and identified the concomitant presence of three missense variations located within the human complement Factor H (CFH) gene cluster. The three variations, rs55807605, rs61737525 and rs57960694, have strong linkage disequilibrium; subsequent haplotype analysis indicated that ATA increased the susceptibility of these renal diseases. In silico analysis, the CFHR3 rs61737525-T risk allele altered the physical and structural properties and generated a reduction in binding affinity of the CFHR3/C3b complex. Surface plasmon resonance (SPR) binding analysis further demonstrated the substitution induced a decrease of two orders of magnitude in C3b-binding properties, with a declined cofactor activity in fluid phase. These data suggest that the haplotype carrying the causative allele behaves as a partial C3 convertase deficiency, predisposing individuals to diverse pathologic lesions underlying complement overactivation. Such genotype-phenotype discrepancies allow better understanding about these nephropathies mediated by genetic complement disorders.
format article
author Yin Ding
Weiwei Zhao
Tao Zhang
Hao Qiang
Jianping Lu
Xin Su
Shuzhen Wen
Feng Xu
Mingchao Zhang
Haitao Zhang
Caihong Zeng
Zhihong Liu
Huimei Chen
author_facet Yin Ding
Weiwei Zhao
Tao Zhang
Hao Qiang
Jianping Lu
Xin Su
Shuzhen Wen
Feng Xu
Mingchao Zhang
Haitao Zhang
Caihong Zeng
Zhihong Liu
Huimei Chen
author_sort Yin Ding
title A haplotype in CFH family genes confers high risk of rare glomerular nephropathies
title_short A haplotype in CFH family genes confers high risk of rare glomerular nephropathies
title_full A haplotype in CFH family genes confers high risk of rare glomerular nephropathies
title_fullStr A haplotype in CFH family genes confers high risk of rare glomerular nephropathies
title_full_unstemmed A haplotype in CFH family genes confers high risk of rare glomerular nephropathies
title_sort haplotype in cfh family genes confers high risk of rare glomerular nephropathies
publisher Nature Portfolio
publishDate 2017
url https://doaj.org/article/8b01a17b909c4a4fb5cba79f402d8a1c
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