Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel Disease.
Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel Disease.
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DOI：
10.1016/j.jcmgh.2021.07.001
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发表时间：
2021
影响因子：
7.2
通讯作者：
Lo B
中科院分区：
文献类型：
--
作者：
Al-Shaibi AA;Abdel-Motal UM;Hubrack SZ;Bullock AN;Al-Marri AA;Agrebi N;Al-Subaiey AA;Ibrahim NA;Charles AK;COLORS in IBD-Qatar Study Group;Elawad M;Uhlig HH;Lo B
胃肠道上皮在维持肠道微生物群的稳态中起着至关重要的作用。粘蛋白对肠道屏障功能至关重要，并作为抗菌因子的支架。粘蛋白2 （MUC2）是主要由杯状细胞产生的肠凝胶状粘蛋白。杯状细胞表达前梯度2 (AGR2)，这是一种蛋白质二硫异构酶，对凝胶形成粘蛋白的正常加工至关重要。在这里，我们调查了两名表现出严重的婴儿性炎症性肠病的兄弟姐妹。我们进行了全基因组测序以确定候选变异。我们使用H&E组织学定量杯状细胞数量，并使用免疫组织化学研究凝胶形成粘蛋白、应激标志物和杯状细胞标志物的表达。采用共免疫沉淀法评价AGR2-MUC2的结合。利用tunicamycin诱导人胚胎肾293T （HEK293T）表达研究突变体AGR2内质网（ER）应激调节功能。两个受影响的兄弟姐妹都是AGR2错义变体的纯合子。患者活检标本显示杯状细胞减少；MUC2、MUC5AC和MUC6的缺失；AGR2上调；内质网应激增加。突变体AGR2显示出结合MUC2和减轻tunicamycin诱导的内质网应激的能力降低。表型-基因型分离、功能实验以及人类表型与AGR2-/-小鼠模型的惊人相似性表明，AGR2错义变异具有致病性。AGR2的孟德尔缺乏症，被称为“由AGR2缺乏症、杯状细胞丢失和内质网应激引起的肠病”（EAGLES），导致粘液屏障缺陷，无法减轻内质网应激，并导致婴儿发病的炎症性肠病。
The gastrointestinal epithelium plays a crucial role in maintaining homeostasis with the gut microbiome. Mucins are essential for intestinal barrier function and serve as a scaffold for antimicrobial factors. Mucin 2 (MUC2) is the major intestinal gel-forming mucin produced predominantly by goblet cells. Goblet cells express anterior gradient 2 (AGR2), a protein disulfide isomerase that is crucial for proper processing of gel-forming mucins. Here, we investigated 2 siblings who presented with severe infantile-onset inflammatory bowel disease. We performed whole-genome sequencing to identify candidate variants. We quantified goblet cell numbers using H&E histology and investigated the expression of gel-forming mucins, stress markers, and goblet cell markers using immunohistochemistry. AGR2-MUC2 binding was evaluated using co-immunoprecipitation. Endoplasmic reticulum (ER) stress regulatory function of mutant AGR2 was examined by expression studies in Human Embryonic Kidney 293T (HEK293T) using tunicamycin to induce ER stress. Both affected siblings were homozygous for a missense variant in AGR2. Patient biopsy specimens showed reduced goblet cells; depletion of MUC2, MUC5AC, and MUC6; up-regulation of AGR2; and increased ER stress. The mutant AGR2 showed reduced capacity to bind MUC2 and alleviate tunicamycin-induced ER stress. Phenotype–genotype segregation, functional experiments, and the striking similarity of the human phenotype to AGR2-/- mouse models suggest that the AGR2 missense variant is pathogenic. The Mendelian deficiency of AGR2, termed “Enteropathy caused by AGR2 deficiency, Goblet cell Loss, and ER Stress” (EAGLES), results in a mucus barrier defect, the inability to mitigate ER stress, and causes infantile-onset inflammatory bowel disease.
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影响因子：
30.8
作者：
通讯作者：
--
影响因子：
29.4
作者：
Uhlig HH;Schwerd T;Koletzko S;Shah N;Kammermeier J;Elkadri A;Ouahed J;Wilson DC;Travis SP;Turner D;Klein C;Snapper SB;Muise AM;COLORS in IBD Study Group and NEOPICS
通讯作者：
COLORS in IBD Study Group and NEOPICS
DOI：
10.1016/s0167-4781(99)00010-x
发表时间：
1999-03-19
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION
影响因子：
--
作者：
Komiya, T;Tanigawa, Y;Hirohashi, S
通讯作者：
Hirohashi, S
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
15.8
作者：
Heazlewood CK;Cook MC;Eri R;Price GR;Tauro SB;Taupin D;Thornton DJ;Png CW;Crockford TL;Cornall RJ;Adams R;Kato M;Nelms KA;Hong NA;Florin TH;Goodnow CC;McGuckin MA
通讯作者：
McGuckin MA