NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease.
NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease.
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DOI：
10.1038/mi.2017.74
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发表时间：
2018-03
影响因子：
8
通讯作者：
Uhlig HH
中科院分区：
文献类型：
--
作者：
Schwerd T;Bryant RV;Pandey S;Capitani M;Meran L;Cazier JB;Jung J;Mondal K;Parkes M;Mathew CG;Fiedler K;McCarthy DJ;WGS500 Consortium;Oxford IBD cohort study investigators;COLORS in IBD group investigators;UK IBD Genetics Consortium;Sullivan PB;Rodrigues A;Travis SPL;Moore C;Sambrook J;Ouwehand WH;Roberts DJ;Danesh J;INTERVAL Study;Russell RK;Wilson DC;Kelsen JR;Cornall R;Denson LA;Kugathasan S;Knaus UG;Serra EG;Anderson CA;Duerr RH;McGovern DP;Cho J;Powrie F;Li VS;Muise AM;Uhlig HH
影响肠上皮屏障功能的遗传缺陷可表现为极早发型炎症性肠病（VE0IBD）。使用全基因组测序，在溃疡性结肠炎样VEOIBD患者中鉴定了编码NAPDH氧化酶1的NOX1的新型半合子缺陷。对1，878名儿科患者进行的外显子组筛查发现了另外7名具有罕见NOX1突变的男性IBD患者。在p.N122H和p.T497A中验证了功能丧失，在p.Y470H、p.R287Q、p.I67M、p.Q293R以及先前描述的p.P330S和常见NOX1 SNP p.D360N（rs34688635）变体中验证了较低程度的功能丧失。错义突变p.N122H消除了细胞系、离体结肠外植体和患者来源的结肠类器官培养物中的活性氧（ROS）产生。在结肠隐窝内，NOX 1在隐窝腔中组成性地产生高水平的ROS。对9，513名对照和11，140名非犹太欧洲血统的IBD患者的分析没有显示p.D360N和IBD之间的关联。我们的数据表明，NOX1的功能丧失变体不会导致孟德尔式的高表达障碍，而是一种环境特异性修饰剂。我们的研究结果表明，NOX1的变体改变了上皮和管腔微生物之间界面处结肠隐窝内的刷状缘ROS。
Genetic defects that affect intestinal epithelial barrier function can present with very early onset inflammatory bowel disease (VEOIBD). Using whole genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 paediatric patients identified further seven male IBD patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex-vivo colonic explants and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.
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影响因子：
4
作者：
Gianni, Davide;Taulet, Nicolas;Zhang, Hui;DerMardirossian, Celine;Kister, Jeremy;Martinez, Luis;Roush, William R.;Brown, Steven J.;Bokoch, Gary M.;Rosen, Hugh
通讯作者：
Rosen, Hugh
影响因子：
14.8
作者：
Clarke, Geraldine M.;Anderson, Carl A.;Pettersson, Fredrik H.;Cardon, Lon R.;Morris, Andrew P.;Zondervan, Krina T.
通讯作者：
Zondervan, Krina T.
影响因子：
5.3
作者：
Coant, Nicolas;Ben Mkaddem, Sanae;Ogier-Denis, Eric
通讯作者：
Ogier-Denis, Eric
DOI：
10.1016/j.bbrc.2010.08.037
发表时间：
2010-09-10
影响因子：
3.1
作者：
Flores, Maria Vega;Crawford, Katie C.;Crosier, Philip S.
通讯作者：
Crosier, Philip S.
影响因子：
158.5
作者：
Fiskerstrand, Torunn;Arshad, Najla;Knappskog, Per M.
通讯作者：
Knappskog, Per M.