Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel Disease
<h3>Background & Aims</h3><p dir="ltr">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 th...
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2021
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| _version_ | 1864513516104318976 |
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| author | Ahmad A. Al-Shaibi (18552234) |
| author2 | Ussama M. Abdel-Motal (138406) Satanay Z. Hubrack (18552236) Alex N. Bullock (18552237) Amna A. Al-Marri (18552239) Nourhen Agrebi (14151222) Abdulrahman A. Al-Subaiey (18552242) Nazira A. Ibrahim (18552247) Adrian K. Charles (112557) Mamoun Elawad (438979) Holm H. Uhlig (564856) Bernice Lo (3441317) |
| author2_role | author author author author author author author author author author author |
| author_facet | Ahmad A. Al-Shaibi (18552234) Ussama M. Abdel-Motal (138406) Satanay Z. Hubrack (18552236) Alex N. Bullock (18552237) Amna A. Al-Marri (18552239) Nourhen Agrebi (14151222) Abdulrahman A. Al-Subaiey (18552242) Nazira A. Ibrahim (18552247) Adrian K. Charles (112557) Mamoun Elawad (438979) Holm H. Uhlig (564856) Bernice Lo (3441317) |
| author_role | author |
| dc.creator.none.fl_str_mv | Ahmad A. Al-Shaibi (18552234) Ussama M. Abdel-Motal (138406) Satanay Z. Hubrack (18552236) Alex N. Bullock (18552237) Amna A. Al-Marri (18552239) Nourhen Agrebi (14151222) Abdulrahman A. Al-Subaiey (18552242) Nazira A. Ibrahim (18552247) Adrian K. Charles (112557) Mamoun Elawad (438979) Holm H. Uhlig (564856) Bernice Lo (3441317) |
| dc.date.none.fl_str_mv | 2021-01-01T06:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1016/j.jcmgh.2021.07.001 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Human_AGR2_Deficiency_Causes_Mucus_Barrier_Dysfunction_and_Infantile_Inflammatory_Bowel_Disease/25816675 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Biochemistry and cell biology Genetics Biomedical and clinical sciences Clinical sciences AGR2 MUC2 ER Stress Intestinal Metaplasia Goblet Cells |
| dc.title.none.fl_str_mv | Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel Disease |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <h3>Background & Aims</h3><p dir="ltr">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.</p><h3>Methods</h3><p dir="ltr">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.</p><h3>Results</h3><p dir="ltr">Both affected siblings were homozygous for a missense variant in <i>AGR2</i> . 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.</p><h3>Conclusions</h3><p dir="ltr">Phenotype–genotype segregation, functional experiments, and the striking similarity of the human phenotype to <i>AGR2</i> <sup><em>-/-</em></sup><sup><em> </em></sup>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.</p><h2>Other Information</h2><p dir="ltr">Published in: Circulation: Cellular and Molecular Gastroenterology and Hepatology<br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://doi.org/10.1016/j.jcmgh.2021.07.001" target="_blank">https://doi.org/10.1016/j.jcmgh.2021.07.001</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_8ab67a846f7f995642cbb0e2786f5d7a |
| identifier_str_mv | 10.1016/j.jcmgh.2021.07.001 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25816675 |
| publishDate | 2021 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel DiseaseAhmad A. Al-Shaibi (18552234)Ussama M. Abdel-Motal (138406)Satanay Z. Hubrack (18552236)Alex N. Bullock (18552237)Amna A. Al-Marri (18552239)Nourhen Agrebi (14151222)Abdulrahman A. Al-Subaiey (18552242)Nazira A. Ibrahim (18552247)Adrian K. Charles (112557)Mamoun Elawad (438979)Holm H. Uhlig (564856)Bernice Lo (3441317)Biological sciencesBiochemistry and cell biologyGeneticsBiomedical and clinical sciencesClinical sciencesAGR2MUC2ER StressIntestinal MetaplasiaGoblet Cells<h3>Background & Aims</h3><p dir="ltr">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.</p><h3>Methods</h3><p dir="ltr">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.</p><h3>Results</h3><p dir="ltr">Both affected siblings were homozygous for a missense variant in <i>AGR2</i> . 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.</p><h3>Conclusions</h3><p dir="ltr">Phenotype–genotype segregation, functional experiments, and the striking similarity of the human phenotype to <i>AGR2</i> <sup><em>-/-</em></sup><sup><em> </em></sup>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.</p><h2>Other Information</h2><p dir="ltr">Published in: Circulation: Cellular and Molecular Gastroenterology and Hepatology<br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://doi.org/10.1016/j.jcmgh.2021.07.001" target="_blank">https://doi.org/10.1016/j.jcmgh.2021.07.001</a></p>2021-01-01T06:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1016/j.jcmgh.2021.07.001https://figshare.com/articles/journal_contribution/Human_AGR2_Deficiency_Causes_Mucus_Barrier_Dysfunction_and_Infantile_Inflammatory_Bowel_Disease/25816675CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/258166752021-01-01T06:00:00Z |
| spellingShingle | Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel Disease Ahmad A. Al-Shaibi (18552234) Biological sciences Biochemistry and cell biology Genetics Biomedical and clinical sciences Clinical sciences AGR2 MUC2 ER Stress Intestinal Metaplasia Goblet Cells |
| status_str | publishedVersion |
| title | Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel Disease |
| title_full | Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel Disease |
| title_fullStr | Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel Disease |
| title_full_unstemmed | Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel Disease |
| title_short | Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel Disease |
| title_sort | Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel Disease |
| topic | Biological sciences Biochemistry and cell biology Genetics Biomedical and clinical sciences Clinical sciences AGR2 MUC2 ER Stress Intestinal Metaplasia Goblet Cells |