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...

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Autores principales:	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, Simon P.L. Travis, Anthony K. Akobeng, Fatma Al-Mudahka
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	AGR2 MUC2 ER Stress Intestinal Metaplasia Goblet Cells Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/5ba41cf384b742d58abb789f5c058425
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spelling	oai:doaj.org-article:5ba41cf384b742d58abb789f5c0584252021-11-12T04:38:47ZHuman AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel DiseaseSummary2352-345X10.1016/j.jcmgh.2021.07.001https://doaj.org/article/5ba41cf384b742d58abb789f5c0584252021-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352345X21001429https://doaj.org/toc/2352-345XBackground & 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.Ahmad A. Al-ShaibiUssama M. Abdel-MotalSatanay Z. HubrackAlex N. BullockAmna A. Al-MarriNourhen AgrebiAbdulrahman A. Al-SubaieyNazira A. IbrahimAdrian K. CharlesMamoun ElawadHolm H. UhligBernice LoSaad R. Al-KaabiMuneera J. Al-MohannadiFayaz A. MirHolm H. UhligSimon P.L. TravisMamoun ElawadAnthony K. AkobengNazira A. IbrahimFatma Al-MudahkaBernice LoElsevierarticleAGR2MUC2ER StressIntestinal MetaplasiaGoblet CellsDiseases of the digestive system. GastroenterologyRC799-869ENCellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 5, Pp 1809-1830 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	AGR2 MUC2 ER Stress Intestinal Metaplasia Goblet Cells Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	AGR2 MUC2 ER Stress Intestinal Metaplasia Goblet Cells Diseases of the digestive system. Gastroenterology RC799-869 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
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.
format	article
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
title	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_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_sort	human agr2 deficiency causes mucus barrier dysfunction and infantile inflammatory bowel diseasesummary
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/5ba41cf384b742d58abb789f5c058425
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Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel DiseaseSummary

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