Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel DiseaseSummary
Background & Aims: 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 produce...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X21001429 |
| _version_ | 1818837607044349952 |
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| author | Ahmad A. Al-Shaibi Ussama M. Abdel-Motal Satanay Z. Hubrack Alex N. Bullock Amna A. Al-Marri Nourhen Agrebi Abdulrahman A. Al-Subaiey Nazira A. Ibrahim Adrian K. Charles Mamoun Elawad Holm H. Uhlig Bernice Lo Saad R. Al-Kaabi Muneera J. Al-Mohannadi Fayaz A. Mir Holm H. Uhlig Simon P.L. Travis Mamoun Elawad Anthony K. Akobeng Nazira A. Ibrahim Fatma Al-Mudahka Bernice Lo |
| author_facet | Ahmad A. Al-Shaibi Ussama M. Abdel-Motal Satanay Z. Hubrack Alex N. Bullock Amna A. Al-Marri Nourhen Agrebi Abdulrahman A. Al-Subaiey Nazira A. Ibrahim Adrian K. Charles Mamoun Elawad Holm H. Uhlig Bernice Lo Saad R. Al-Kaabi Muneera J. Al-Mohannadi Fayaz A. Mir Holm H. Uhlig Simon P.L. Travis Mamoun Elawad Anthony K. Akobeng Nazira A. Ibrahim Fatma Al-Mudahka Bernice Lo |
| author_sort | Ahmad A. Al-Shaibi |
| collection | DOAJ |
| description | Background & Aims: 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. Methods: 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. Results: 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. Conclusions: 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. |
| first_indexed | 2024-12-19T03:25:11Z |
| format | Article |
| id | doaj.art-5ba41cf384b742d58abb789f5c058425 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-19T03:25:11Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-5ba41cf384b742d58abb789f5c0584252022-12-21T20:37:38ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2021-01-0112518091830Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel DiseaseSummaryAhmad A. Al-Shaibi0Ussama M. Abdel-Motal1Satanay Z. Hubrack2Alex N. Bullock3Amna A. Al-Marri4Nourhen Agrebi5Abdulrahman A. Al-Subaiey6Nazira A. Ibrahim7Adrian K. Charles8Mamoun Elawad9Holm H. Uhlig10Bernice Lo11Saad R. Al-KaabiMuneera J. Al-MohannadiFayaz A. MirHolm H. UhligSimon P.L. TravisMamoun ElawadAnthony K. AkobengNazira A. IbrahimFatma Al-MudahkaBernice LoResearch Branch, Sidra Medicine, Doha, QatarResearch Branch, Sidra Medicine, Doha, QatarResearch Branch, Sidra Medicine, Doha, QatarCentre for Medicines Discovery, University of Oxford, Oxford, United KingdomResearch Branch, Sidra Medicine, Doha, QatarResearch Branch, Sidra Medicine, Doha, QatarCollege of Health and Life Sciences, Hamad Bin Khalifa University, Doha, QatarDepartment of Gastroenterology, Sidra Medicine, Doha, QatarDepartment of Anatomical Pathology, Sidra Medicine, Doha, QatarDepartment of Gastroenterology, Sidra Medicine, Doha, QatarTranslational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; Oxford Biomedical Research Centre, Oxford, United Kingdom; Department of Pediatrics, University of Oxford, Oxford, United KingdomResearch Branch, Sidra Medicine, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar; Correspondence Address correspondence to: Bernice Lo, PhD, Sidra Medicine, PO Box 26999, Doha, Qatar.Background & Aims: 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. Methods: 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. Results: 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. Conclusions: 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.http://www.sciencedirect.com/science/article/pii/S2352345X21001429AGR2MUC2ER StressIntestinal MetaplasiaGoblet Cells |
| spellingShingle | Ahmad A. Al-Shaibi Ussama M. Abdel-Motal Satanay Z. Hubrack Alex N. Bullock Amna A. Al-Marri Nourhen Agrebi Abdulrahman A. Al-Subaiey Nazira A. Ibrahim Adrian K. Charles Mamoun Elawad Holm H. Uhlig Bernice Lo Saad R. Al-Kaabi Muneera J. Al-Mohannadi Fayaz A. Mir Holm H. Uhlig Simon P.L. Travis Mamoun Elawad Anthony K. Akobeng Nazira A. Ibrahim Fatma Al-Mudahka Bernice Lo Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel DiseaseSummary Cellular and Molecular Gastroenterology and Hepatology AGR2 MUC2 ER Stress Intestinal Metaplasia Goblet Cells |
| title | Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel DiseaseSummary |
| title_full | Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel DiseaseSummary |
| title_fullStr | Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel DiseaseSummary |
| title_full_unstemmed | Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel DiseaseSummary |
| title_short | Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel DiseaseSummary |
| title_sort | human agr2 deficiency causes mucus barrier dysfunction and infantile inflammatory bowel diseasesummary |
| topic | AGR2 MUC2 ER Stress Intestinal Metaplasia Goblet Cells |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X21001429 |
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