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2,324 results on '"Holm, H"'

1. A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease

Author

Thomas, Tom, Friedrich, Matthias, Rich-Griffin, Charlotte, Pohin, Mathilde, Agarwal, Devika, Pakpoor, Julia, Lee, Carl, Tandon, Ruchi, Rendek, Aniko, Aschenbrenner, Dominik, Jainarayanan, Ashwin, Voda, Alexandru, Siu, Jacqueline H. Y., Sanches-Peres, Raphael, Nee, Eloise, Sathananthan, Dharshan, Kotliar, Dylan, Todd, Peter, Kiourlappou, Maria, Gartner, Lisa, Ilott, Nicholas, Issa, Fadi, Hester, Joanna, Turner, Jason, Nayar, Saba, Mackerodt, Jonas, Zhang, Fan, Jonsson, Anna, Brenner, Michael, Raychaudhuri, Soumya, Kulicke, Ruth, Ramsdell, Danielle, Stransky, Nicolas, Pagliarini, Ray, Bielecki, Piotr, Spies, Noah, Marsden, Brian, Taylor, Stephen, Wagner, Allon, Klenerman, Paul, Walsh, Alissa, Coles, Mark, Jostins-Dean, Luke, Powrie, Fiona M., Filer, Andrew, Travis, Simon, Uhlig, Holm H., Dendrou, Calliope A., and Buckley, Christopher D.

Published
2024
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4. Identification and validation of a blood- based diagnostic lipidomic signature of pediatric inflammatory bowel disease

Author

Salihovic, Samira, Nyström, Niklas, Mathisen, Charlotte Bache-Wiig, Kruse, Robert, Olbjørn, Christine, Andersen, Svend, Noble, Alexandra J., Dorn-Rasmussen, Maria, Bazov, Igor, Perminow, Gøri, Opheim, Randi, Detlie, Trond Espen, Huppertz-Hauss, Gert, Hedin, Charlotte R. H., Carlson, Marie, Öhman, Lena, Magnusson, Maria K., Keita, Åsa V., Söderholm, Johan D., D’Amato, Mauro, Orešič, Matej, Wewer, Vibeke, Satsangi, Jack, Lindqvist, Carl Mårten, Burisch, Johan, Uhlig, Holm H., Repsilber, Dirk, Hyötyläinen, Tuulia, Høivik, Marte Lie, and Halfvarson, Jonas

Published
2024
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6. Identification and validation of a blood- based diagnostic lipidomic signature of pediatric inflammatory bowel disease

Author

Samira Salihovic, Niklas Nyström, Charlotte Bache-Wiig Mathisen, Robert Kruse, Christine Olbjørn, Svend Andersen, Alexandra J. Noble, Maria Dorn-Rasmussen, Igor Bazov, Gøri Perminow, Randi Opheim, Trond Espen Detlie, Gert Huppertz-Hauss, Charlotte R. H. Hedin, Marie Carlson, Lena Öhman, Maria K. Magnusson, Åsa V. Keita, Johan D. Söderholm, Mauro D’Amato, Matej Orešič, Vibeke Wewer, Jack Satsangi, Carl Mårten Lindqvist, Johan Burisch, Holm H. Uhlig, Dirk Repsilber, Tuulia Hyötyläinen, Marte Lie Høivik, and Jonas Halfvarson

Subjects
Science
Abstract

Abstract Improved biomarkers are needed for pediatric inflammatory bowel disease. Here we identify a diagnostic lipidomic signature for pediatric inflammatory bowel disease by analyzing blood samples from a discovery cohort of incident treatment-naïve pediatric patients and validating findings in an independent inception cohort. The lipidomic signature comprising of only lactosyl ceramide (d18:1/16:0) and phosphatidylcholine (18:0p/22:6) improves the diagnostic prediction compared with high-sensitivity C-reactive protein. Adding high-sensitivity C-reactive protein to the signature does not improve its performance. In patients providing a stool sample, the diagnostic performance of the lipidomic signature and fecal calprotectin, a marker of gastrointestinal inflammation, does not substantially differ. Upon investigation in a third pediatric cohort, the findings of increased lactosyl ceramide (d18:1/16:0) and decreased phosphatidylcholine (18:0p/22:6) absolute concentrations are confirmed. Translation of the lipidomic signature into a scalable diagnostic blood test for pediatric inflammatory bowel disease has the potential to support clinical decision making.

Published
2024
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7. An isoform quantitative trait locus in SBNO2 links genetic susceptibility to Crohn’s disease with defective antimicrobial activity

Author

Dominik Aschenbrenner, Isar Nassiri, Suresh Venkateswaran, Sumeet Pandey, Matthew Page, Lauren Drowley, Martin Armstrong, Subra Kugathasan, Benjamin Fairfax, and Holm H. Uhlig

Subjects
Science
Abstract

Abstract Despite major advances in linking single genetic variants to single causal genes, the significance of genetic variation on transcript-level regulation of expression, transcript-specific functions, and relevance to human disease has been poorly investigated. Strawberry notch homolog 2 (SBNO2) is a candidate gene in a susceptibility locus with different variants associated with Crohn’s disease and bone mineral density. The SBNO2 locus is also differentially methylated in Crohn’s disease but the functional mechanisms are unknown. Here we show that the isoforms of SBNO2 are differentially regulated by lipopolysaccharide and IL-10. We identify Crohn’s disease associated isoform quantitative trait loci that negatively regulate the expression of the noncanonical isoform 2 corresponding with the methylation signals at the isoform 2 promoter in IBD and CD. The two isoforms of SBNO2 drive differential gene networks with isoform 2 dominantly impacting antimicrobial activity in macrophages. Our data highlight the role of isoform quantitative trait loci to understand disease susceptibility and resolve underlying mechanisms of disease.

Published
2024
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8. Precision medicine in monogenic inflammatory bowel disease: proposed mIBD REPORT standards

Author

Uhlig, Holm H., Booth, Claire, Cho, Judy, Dubinsky, Marla, Griffiths, Anne M., Grimbacher, Bodo, Hambleton, Sophie, Huang, Ying, Jones, Kelsey, Kammermeier, Jochen, Kanegane, Hirokazu, Koletzko, Sibylle, Kotlarz, Daniel, Klein, Christoph, Lenardo, Michael J., Lo, Bernice, McGovern, Dermot P. B., Özen, Ahmet, de Ridder, Lissy, Ruemmele, Frank, Shouval, Dror S., Snapper, Scott B., Travis, Simon P., Turner, Dan, Wilson, David C., and Muise, Aleixo M.

Published
2023
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10. Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases

Author

Alistair T. Pagnamenta, Carme Camps, Edoardo Giacopuzzi, John M. Taylor, Mona Hashim, Eduardo Calpena, Pamela J. Kaisaki, Akiko Hashimoto, Jing Yu, Edward Sanders, Ron Schwessinger, Jim R. Hughes, Gerton Lunter, Helene Dreau, Matteo Ferla, Lukas Lange, Yesim Kesim, Vassilis Ragoussis, Dimitrios V. Vavoulis, Holger Allroggen, Olaf Ansorge, Christian Babbs, Siddharth Banka, Benito Baños-Piñero, David Beeson, Tal Ben-Ami, David L. Bennett, Celeste Bento, Edward Blair, Charlotte Brasch-Andersen, Katherine R. Bull, Holger Cario, Deirdre Cilliers, Valerio Conti, E. Graham Davies, Fatima Dhalla, Beatriz Diez Dacal, Yin Dong, James E. Dunford, Renzo Guerrini, Adrian L. Harris, Jane Hartley, Georg Hollander, Kassim Javaid, Maureen Kane, Deirdre Kelly, Dominic Kelly, Samantha J. L. Knight, Alexandra Y. Kreins, Erika M. Kvikstad, Craig B. Langman, Tracy Lester, Kate E. Lines, Simon R. Lord, Xin Lu, Sahar Mansour, Adnan Manzur, Reza Maroofian, Brian Marsden, Joanne Mason, Simon J. McGowan, Davide Mei, Hana Mlcochova, Yoshiko Murakami, Andrea H. Németh, Steven Okoli, Elizabeth Ormondroyd, Lilian Bomme Ousager, Jacqueline Palace, Smita Y. Patel, Melissa M. Pentony, Chris Pugh, Aboulfazl Rad, Archana Ramesh, Simone G. Riva, Irene Roberts, Noémi Roy, Outi Salminen, Kyleen D. Schilling, Caroline Scott, Arjune Sen, Conrad Smith, Mark Stevenson, Rajesh V. Thakker, Stephen R. F. Twigg, Holm H. Uhlig, Richard van Wijk, Barbara Vona, Steven Wall, Jing Wang, Hugh Watkins, Jaroslav Zak, Anna H. Schuh, Usha Kini, Andrew O. M. Wilkie, Niko Popitsch, and Jenny C. Taylor

Subjects
Genome sequencing, Rare diseases, Structural variant, Splice site variant, Non-coding, Diagnostic yield, Medicine, Genetics, QH426-470
Abstract

Abstract Background Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25–30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome. Methods We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants. Results Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving. Conclusions Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing.

Published
2023
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11. The impact of inversions across 33,924 families with rare disease from a national genome sequencing project

Author

Pagnamenta, Alistair T., Yu, Jing, Walker, Susan, Noble, Alexandra J., Lord, Jenny, Dutta, Prasun, Hashim, Mona, Camps, Carme, Green, Hannah, Devaiah, Smrithi, Nashef, Lina, Parr, Jason, Fratter, Carl, Ibnouf Hussein, Rana, Lindsay, Sarah J., Lalloo, Fiona, Banos-Pinero, Benito, Evans, David, Mallin, Lucy, Waite, Adrian, Evans, Julie, Newman, Andrew, Allen, Zoe, Perez-Becerril, Cristina, Ryan, Gavin, Hart, Rachel, Taylor, John, Bedenham, Tina, Clement, Emma, Blair, Ed, Hay, Eleanor, Forzano, Francesca, Higgs, Jenny, Canham, Natalie, Majumdar, Anirban, McEntagart, Meriel, Lahiri, Nayana, Stewart, Helen, Smithson, Sarah, Calpena, Eduardo, Jackson, Adam, Banka, Siddharth, Titheradge, Hannah, McGowan, Ruth, Rankin, Julia, Shaw-Smith, Charles, Evans, D. Gareth, Burghel, George J., Smith, Miriam J., Anderson, Emily, Madhu, Rajesh, Firth, Helen, Ellard, Sian, Brennan, Paul, Anderson, Claire, Taupin, Doug, Rogers, Mark T., Cook, Jackie A., Durkie, Miranda, East, James E., Fowler, Darren, Wilson, Louise, Igbokwe, Rebecca, Gardham, Alice, Tomlinson, Ian, Baralle, Diana, Uhlig, Holm H., and Taylor, Jenny C.

Published
2024
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12. Biallelic PI4KA variants cause neurological, intestinal and immunological disease

Author

Salter, Claire G, Cai, Yiying, Lo, Bernice, Helman, Guy, Taylor, Henry, McCartney, Amber, Leslie, Joseph S, Accogoli, Andrea, Zara, Frederico, Traverso, Monica, Fasham, James, Lees, Joshua A, Ferla, Matteo, Chioza, Barry A, Wenger, Olivia, Scott, Ethan, Cross, Harold E, Crawford, Joanna, Warshawsky, Ilka, Keisling, Matthew, Agamanolis, Dimitris, Melver, Catherine Ward, Cox, Helen, Elawad, Mamoun, Marton, Tamas, Wakeling, Matthew, Holzinger, Dirk, Tippelt, Stephan, Munteanu, Martin, Valcheva, Deyana, Deal, Christin, Van Meerbeke, Sara, Vockley, Catherine Walsh, Butte, Manish J, Acar, Utkucan, van der Knaap, Marjo S, Korenke, G Christoph, Kotzaeridou, Urania, Balla, Tamas, Simons, Cas, Uhlig, Holm H, Crosby, Andrew H, De Camilli, Pietro, Wolf, Nicole I, and Baple, Emma L

Subjects
Digestive Diseases, Pediatric, 1.1 Normal biological development and functioning, Aetiology, 2.1 Biological and endogenous factors, Underpinning research, Oral and gastrointestinal, Female, Hereditary Central Nervous System Demyelinating Diseases, Humans, Intestinal Atresia, Male, Minor Histocompatibility Antigens, Pedigree, Phosphotransferases (Alcohol Group Acceptor), Polymorphism, Single Nucleotide, Primary Immunodeficiency Diseases, hypomyelinating leukodystrophy, multiple intestinal atresia, PI4KA, FAM126A, TTC7A, PI4KA, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

Phosphatidylinositol 4-kinase IIIα (PI4KIIIα/PI4KA/OMIM:600286) is a lipid kinase generating phosphatidylinositol 4-phosphate (PI4P), a membrane phospholipid with critical roles in the physiology of multiple cell types. PI4KIIIα's role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126. Sequence alterations in two of these molecular partners, TTC7 (encoded by TTC7A or TCC7B) and FAM126, have been associated with a heterogeneous group of either neurological (FAM126A) or intestinal and immunological (TTC7A) conditions. Here we show that biallelic PI4KA sequence alterations in humans are associated with neurological disease, in particular hypomyelinating leukodystrophy. In addition, affected individuals may present with inflammatory bowel disease, multiple intestinal atresia and combined immunodeficiency. Our cellular, biochemical and structural modelling studies indicate that PI4KA-associated phenotypical outcomes probably stem from impairment of PI4KIIIα-TTC7-FAM126's organ-specific functions, due to defective catalytic activity or altered intra-complex functional interactions. Together, these data define PI4KA gene alteration as a cause of a variable phenotypical spectrum and provide fundamental new insight into the combinatorial biology of the PI4KIIIα-FAM126-TTC7-EFR3 molecular complex.

Published
2021

15. A metabolic perspective of the neutrophil life cycle: new avenues in immunometabolism

Author

Mehakpreet K. Thind, Holm H. Uhlig, Michael Glogauer, Nades Palaniyar, Celine Bourdon, Agnes Gwela, Christina L. Lancioni, James A. Berkley, Robert H. J. Bandsma, and Amber Farooqui

Subjects
metabolic reprogramming, neutrophil differentiation, glycolysis, immune mediated diseases, autophagy, mitochondrial respiration, Immunologic diseases. Allergy, RC581-607
Abstract

Neutrophils are the most abundant innate immune cells. Multiple mechanisms allow them to engage a wide range of metabolic pathways for biosynthesis and bioenergetics for mediating biological processes such as development in the bone marrow and antimicrobial activity such as ROS production and NET formation, inflammation and tissue repair. We first discuss recent work on neutrophil development and functions and the metabolic processes to regulate granulopoiesis, neutrophil migration and trafficking as well as effector functions. We then discuss metabolic syndromes with impaired neutrophil functions that are influenced by genetic and environmental factors of nutrient availability and usage. Here, we particularly focus on the role of specific macronutrients, such as glucose, fatty acids, and protein, as well as micronutrients such as vitamin B3, in regulating neutrophil biology and how this regulation impacts host health. A special section of this review primarily discusses that the ways nutrient deficiencies could impact neutrophil biology and increase infection susceptibility. We emphasize biochemical approaches to explore neutrophil metabolism in relation to development and functions. Lastly, we discuss opportunities and challenges to neutrophil-centered therapeutic approaches in immune-driven diseases and highlight unanswered questions to guide future discoveries.

Published
2024
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16. Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases

Author

Pagnamenta, Alistair T., Camps, Carme, Giacopuzzi, Edoardo, Taylor, John M., Hashim, Mona, Calpena, Eduardo, Kaisaki, Pamela J., Hashimoto, Akiko, Yu, Jing, Sanders, Edward, Schwessinger, Ron, Hughes, Jim R., Lunter, Gerton, Dreau, Helene, Ferla, Matteo, Lange, Lukas, Kesim, Yesim, Ragoussis, Vassilis, Vavoulis, Dimitrios V., Allroggen, Holger, Ansorge, Olaf, Babbs, Christian, Banka, Siddharth, Baños-Piñero, Benito, Beeson, David, Ben-Ami, Tal, Bennett, David L., Bento, Celeste, Blair, Edward, Brasch-Andersen, Charlotte, Bull, Katherine R., Cario, Holger, Cilliers, Deirdre, Conti, Valerio, Davies, E. Graham, Dhalla, Fatima, Dacal, Beatriz Diez, Dong, Yin, Dunford, James E., Guerrini, Renzo, Harris, Adrian L., Hartley, Jane, Hollander, Georg, Javaid, Kassim, Kane, Maureen, Kelly, Deirdre, Kelly, Dominic, Knight, Samantha J. L., Kreins, Alexandra Y., Kvikstad, Erika M., Langman, Craig B., Lester, Tracy, Lines, Kate E., Lord, Simon R., Lu, Xin, Mansour, Sahar, Manzur, Adnan, Maroofian, Reza, Marsden, Brian, Mason, Joanne, McGowan, Simon J., Mei, Davide, Mlcochova, Hana, Murakami, Yoshiko, Németh, Andrea H., Okoli, Steven, Ormondroyd, Elizabeth, Ousager, Lilian Bomme, Palace, Jacqueline, Patel, Smita Y., Pentony, Melissa M., Pugh, Chris, Rad, Aboulfazl, Ramesh, Archana, Riva, Simone G., Roberts, Irene, Roy, Noémi, Salminen, Outi, Schilling, Kyleen D., Scott, Caroline, Sen, Arjune, Smith, Conrad, Stevenson, Mark, Thakker, Rajesh V., Twigg, Stephen R. F., Uhlig, Holm H., van Wijk, Richard, Vona, Barbara, Wall, Steven, Wang, Jing, Watkins, Hugh, Zak, Jaroslav, Schuh, Anna H., Kini, Usha, Wilkie, Andrew O. M., Popitsch, Niko, and Taylor, Jenny C.

Published
2023
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17. HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis

Author

Akar, Alaa, Flemming, Cornelius, Felix, Flomm, Flosbach, Markus, Jäger, Julia, Jeromin, Niklas, Jung, Johannes, Ohms, Mareike, Reinshagen, Konrad, Rische, Johann, Sagebiel, Adrian, Sandfort, Deborah, Steinert, Fenja, Tomuschat, Christian, Wesche, Jasmin, Shifteh Abedian, Abraham, Clara, Achkar, Jean-Paul, Ahmad, Tariq, Alberts, Rudi, Alizadeh, Behrooz, Amininejad, Leila, Ananthakrishnan, Ashwin N., Andersen, Vibeke, Anderson, Carl A., Andrews, Jane M., Annese, Vito, Aumais, Guy, Baidoo, Leonard, Baldassano, Robert N., Bampton, Peter A., Barclay, Murray, Barrett, Jeffrey C., Bethge, Johannes, Bewshea, Claire, Bis, Joshua C., Bitton, Alain, BK, Thelma, Boucher, Gabrielle, Brain, Oliver, Brand, Stephan, Brant, Steven R., Cheon, Jae Hee, Chew, Angela, Cho, Judy H., Cleynen, Isabelle, Cohain, Ariella, Cooney, Rachel, Croft, Anthony, Daly, Mark J., D'Amato, Mauro, Danese, Silvio, Daryani, Naser Ebrahim, Datta, Lisa Wu, Degenhardt, Frauke, Denapiene, Goda, Denson, Lee A., Devaney, Kathy L., Dewit, Olivier, D'Inca, Renata, Drummond, Hazel E., Dubinsky, Marla, Duerr, Richard H., Edwards, Cathryn, Ellinghaus, David, Ellul, Pierre, Esaki, Motohiro, Essers, Jonah, Ferguson, Lynnette R., Festen, Eleonora A., Fleshner, Philip, Florin, Tim, Franchimont, Denis, Franke, Andre, Fuyuno, Yuta, Gearry, Richard, Georges, Michel, Gieger, Christian, Glas, Jürgen, Goyette, Philippe, Green, Todd, Griffiths, Anne M., Guthery, Stephen L., Hakonarson, Hakon, Halfvarson, Jonas, Hanigan, Katherine, Haritunians, Talin, Hart, Ailsa, Hawkey, Chris, Hayward, Nicholas K., Hedl, Matija, Henderson, Paul, Hold, Georgina L., Hong, Myhunghee, Hu, Xinli, Huang, Hailiang, Hugot, Jean-Pierre, Hui, Ken Y., Imielinski, Marcin, Jazayeri, Omid, Jonaitis, Laimas, Jostins, Luke, Juyal, Garima, Chandra Juyal, Ramesh, Kalla, Rahul, Karlsen, Tom H., Kennedy, Nicholas A., Khan, Mohammed Azam, Kim, Won Ho, Kitazono, Takanari, Kiudelis, Gediminas, Kubo, Michiaki, Kugathasan, Subra, Kupcinskas, Limas, Lamb, Christopher A., de Lange, Katrina M., Latiano, Anna, Laukens, Debby, Lawrance, Ian C., Lee, James C., Lees, Charlie W., Leja, Marcis, Lewis, Nina, Van Limbergen, Johan, Lionetti, Paolo, Liu, Jimmy Z., Louis, Edouard, Luo, Yang, Mahy, Gillian, Malekzadeh, Masoud Mohammad, Malekzadeh, Reza, Mansfield, John, Marriott, Suzie, Massey, Dunecan, Mathew, Christopher G., Matsui, Toshiyuki, McGovern, Dermot P.B., van der Meulen, Andrea, Midha, Vandana, Milgrom, Raquel, Mirzaei, Samaneh, Mitrovic, Mitja, Montgomery, Grant W., Mowat, Craig, Müller, Christoph, Newman, William G., Ng, Aylwin, Ng, Siew C., Evelyn Ng, Sok Meng, Nikolaus, Susanna, Ning, Kaida, Nöthen, Markus, Oikonomou, Ioannis, Okou, David, Orchard, Timothy R., Palmieri, Orazio, Parkes, Miles, Phillips, Anne, Ponsioen, Cyriel Y., Potocnik, Urõs, Poustchi, Hossein, Prescott, Natalie J., Proctor, Deborah D., Radford-Smith, Graham, Rahier, Jean- Francois, Regueiro, Miguel, Reinisch, Walter, Rieder, Florian, Rioux, John D., Roberts, Rebecca, Rogler, Gerhard, Russell, Richard K., Sanderson, Jeremy D., Sans, Miquel, Satsangi, Jack, Schadt, Eric E., Scharl, Michael, Schembri, John, Schreiber, Stefan, Schumm, L. Philip, Scott, Regan, Seielstad, Mark, Shah, Tejas, Sharma, Yashoda, Silverberg, Mark S., Simmons, Alison, Simms, Lisa A., Singh, Abhey, Skieceviciene, Jurgita, van Sommeren, Suzanne, Song, Kyuyoung, Sood, Ajit, Spain, Sarah L., Steinhart, A. Hillary, Stempak, Joanne M., Stronati, Laura, Sung, Joseph J.Y., Targan, Stephan R., Taylor, Kirstin M., Theatre, Emilie, Torkvist, Leif, Torres, Esther A., Tremelling, Mark, Uhlig, Holm H., Umeno, Junji, Vahedi, Homayon, Vasiliauskas, Eric, Velde, Anje ter, Ventham, Nicholas T., Vermeire, Severine, Verspaget, Hein W., De Vos, Martine, Walters, Thomas, Wang, Kai, Wang, Ming-Hsi, Weersma, Rinse K., Wei, Zhi, Whiteman, David, Wijmenga, Cisca, Wilson, David C., Winkelmann, Juliane, Wong, Sunny H., Xavier, Ramnik J., Yamazaki, Keiko, Yang, Suk-Kyun, Ye, Byong Duk, Zeissig, Sebastian, Zhang, Bin, Zhang, Clarence K., Zhang, Hu, Zhang, Wei, Zhao, Hongyu, Zhao, Zhen Z., Baumdick, Martin E., Niehrs, Annika, Schwerk, Maria, Hinrichs, Ole, Jordan-Paiz, Ana, Padoan, Benedetta, Wegner, Lucy H.M., Schloer, Sebastian, Zecher, Britta F., Malsy, Jakob, Joshi, Vinita R., Illig, Christin, Schröder-Schwarz, Jennifer, Möller, Kimberly J., Martin, Maureen P., Yuki, Yuko, Ozawa, Mikki, Sauter, Jürgen, Schmidt, Alexander H., Perez, Daniel, Giannou, Anastasios D., Carrington, Mary, Davis, Randall S., Schumacher, Udo, Sauter, Guido, Huber, Samuel, Puelles, Victor G., Melling, Nathaniel, Altfeld, Marcus, and Bunders, Madeleine J.

Published
2023
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21. Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.

Author

Béziat, Vivien, Tavernier, Simon J, Chen, Yin-Huai, Ma, Cindy S, Materna, Marie, Laurence, Arian, Staal, Jens, Aschenbrenner, Dominik, Roels, Lisa, Worley, Lisa, Claes, Kathleen, Gartner, Lisa, Kohn, Lisa A, De Bruyne, Marieke, Schmitz-Abe, Klaus, Charbonnier, Louis-Marie, Keles, Sevgi, Nammour, Justine, Vladikine, Natasha, Maglorius Renkilaraj, Majistor Raj Luxman, Seeleuthner, Yoann, Migaud, Mélanie, Rosain, Jérémie, Jeljeli, Mohamed, Boisson, Bertrand, Van Braeckel, Eva, Rosenfeld, Jill A, Dai, Hongzheng, Burrage, Lindsay C, Murdock, David R, Lambrecht, Bart N, Avettand-Fenoel, Véronique, Vogel, Tiphanie P, Undiagnosed Diseases Network, Esther, Charles R, Haskologlu, Sule, Dogu, Figen, Ciznar, Peter, Boutboul, David, Ouachée-Chardin, Marie, Amourette, Jean, Lebras, Marie-Noëlle, Gauvain, Clément, Tcherakian, Colas, Ikinciogullari, Aydan, Beyaert, Rudi, Abel, Laurent, Milner, Joshua D, Grimbacher, Bodo, Couderc, Louis-Jean, Butte, Manish J, Freeman, Alexandra F, Catherinot, Émilie, Fieschi, Claire, Chatila, Talal A, Tangye, Stuart G, Uhlig, Holm H, Haerynck, Filomeen, Casanova, Jean-Laurent, and Puel, Anne

Subjects
Undiagnosed Diseases Network, Th2 Cells, Cells, Cultured, Cell Membrane, Fibroblasts, Humans, C-Reactive Protein, Cytokines, Pedigree, Genetics, Population, Up-Regulation, Kinetics, Genes, Dominant, Phenotype, Mutation, Alleles, Models, Biological, Adolescent, Middle Aged, Child, Female, Male, Cytokine Receptor gp130, Young Adult, HEK293 Cells, Job Syndrome, Loss of Function Mutation, Cells, Cultured, Genetics, Population, Genes, Dominant, Models, Biological, Medical and Health Sciences, Immunology
Abstract

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients' heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

Published
2020

23. Genomic diagnosis and care co-ordination for monogenic inflammatory bowel disease in children and adults: consensus guideline on behalf of the British Society of Gastroenterology and British Society of Paediatric Gastroenterology, Hepatology and Nutrition

Author

Kammermeier, Jochen, Lamb, Christopher A, Jones, Kelsey D J, Anderson, Carl A, Baple, Emma L, Bolton, Chrissy, Braggins, Helen, Coulter, Tanya I, Gilmour, Kimberly C, Gregory, Vicki, Hambleton, Sophie, Hartley, David, Hawthorne, A Barney, Hearn, Sarah, Laurence, Arian, Parkes, Miles, Russell, Richard K, Speight, R Alexander, Travis, Simon, Wilson, David C, and Uhlig, Holm H

Published
2023
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24. A conserved population of MHC II-restricted, innate-like, commensal-reactive T cells in the gut of humans and mice

Author

Carl-Philipp Hackstein, Dana Costigan, Linnea Drexhage, Claire Pearson, Samuel Bullers, Nicholas Ilott, Hossain Delowar Akther, Yisu Gu, Michael E. B. FitzPatrick, Oliver J. Harrison, Lucy C. Garner, Elizabeth H. Mann, Sumeet Pandey, Matthias Friedrich, Nicholas M. Provine, Holm H. Uhlig, Emanuele Marchi, Fiona Powrie, Paul Klenerman, and Emily E. Thornton

Subjects
Science
Abstract

Interactions between the host immune response and the commensal microbiota play essential roles in health and disease. Here the authors identify a population of MHC class II, innate like, commensal reactive cells in the gut of mice and humans.

Published
2022
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25. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility

Author

Sazonovs, Aleksejs, Stevens, Christine R., Venkataraman, Guhan R., Yuan, Kai, Avila, Brandon, Abreu, Maria T., Ahmad, Tariq, Allez, Matthieu, Ananthakrishnan, Ashwin N., Atzmon, Gil, Baras, Aris, Barrett, Jeffrey C., Barzilai, Nir, Beaugerie, Laurent, Beecham, Ashley, Bernstein, Charles N., Bitton, Alain, Bokemeyer, Bernd, Chan, Andrew, Chung, Daniel, Cleynen, Isabelle, Cosnes, Jacques, Cutler, David J., Daly, Allan, Damas, Oriana M., Datta, Lisa W., Dawany, Noor, Devoto, Marcella, Dodge, Sheila, Ellinghaus, Eva, Fachal, Laura, Farkkila, Martti, Faubion, William, Ferreira, Manuel, Franchimont, Denis, Gabriel, Stacey B., Ge, Tian, Georges, Michel, Gettler, Kyle, Giri, Mamta, Glaser, Benjamin, Goerg, Siegfried, Goyette, Philippe, Graham, Daniel, Hämäläinen, Eija, Haritunians, Talin, Heap, Graham A., Hiltunen, Mikko, Hoeppner, Marc, Horowitz, Julie E., Irving, Peter, Iyer, Vivek, Jalas, Chaim, Kelsen, Judith, Khalili, Hamed, Kirschner, Barbara S., Kontula, Kimmo, Koskela, Jukka T., Kugathasan, Subra, Kupcinskas, Juozas, Lamb, Christopher A., Laudes, Matthias, Lévesque, Chloé, Levine, Adam P., Lewis, James D., Liefferinckx, Claire, Loescher, Britt-Sabina, Louis, Edouard, Mansfield, John, May, Sandra, McCauley, Jacob L., Mengesha, Emebet, Mni, Myriam, Moayyedi, Paul, Moran, Christopher J., Newberry, Rodney D., O’Charoen, Sirimon, Okou, David T., Oldenburg, Bas, Ostrer, Harry, Palotie, Aarno, Paquette, Jean, Pekow, Joel, Peter, Inga, Pierik, Marieke J., Ponsioen, Cyriel Y., Pontikos, Nikolas, Prescott, Natalie, Pulver, Ann E., Rahmouni, Souad, Rice, Daniel L., Saavalainen, Päivi, Sands, Bruce, Sartor, R. Balfour, Schiff, Elena R., Schreiber, Stefan, Schumm, L. Philip, Segal, Anthony W., Seksik, Philippe, Shawky, Rasha, Sheikh, Shehzad Z., Silverberg, Mark S., Simmons, Alison, Skeiceviciene, Jurgita, Sokol, Harry, Solomonson, Matthew, Somineni, Hari, Sun, Dylan, Targan, Stephan, Turner, Dan, Uhlig, Holm H., van der Meulen, Andrea E., Vermeire, Séverine, Verstockt, Sare, Voskuil, Michiel D., Winter, Harland S., Young, Justine, Duerr, Richard H., Franke, Andre, Brant, Steven R., Cho, Judy, Weersma, Rinse K., Parkes, Miles, Xavier, Ramnik J., Rivas, Manuel A., Rioux, John D., McGovern, Dermot P. B., Huang, Hailiang, Anderson, Carl A., and Daly, Mark J.

Published
2022
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26. Hermansky-Pudlak syndrome type 1 causes impaired anti-microbial immunity and inflammation due to dysregulated immunometabolism

Author

Cavounidis, Athena, Pandey, Sumeet, Capitani, Melania, Friedrich, Matthias, Cross, Amy, Gartner, Lisa, Aschenbrenner, Dominik, Kim-Schulze, Seunghee, Lam, Ying Ka, Berridge, Georgina, McGovern, Dermot P. B., Kessler, Benedikt, Fischer, Roman, Klenerman, Paul, Hester, Joanna, Issa, Fadi, Torres, Esther A., Powrie, Fiona, Gochuico, Bernadette R., Gahl, William A., Cohen, Louis, and Uhlig, Holm H.

Published
2022
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29. An Integrated Taxonomy for Monogenic Inflammatory Bowel Disease

Author

Bolton, Chrissy, Smillie, Christopher S., Pandey, Sumeet, Elmentaite, Rasa, Wei, Gabrielle, Argmann, Carmen, Aschenbrenner, Dominik, James, Kylie R., McGovern, Dermot P.B., Macchi, Marina, Cho, Judy, Shouval, Dror S., Kammermeier, Jochen, Koletzko, Sibylle, Bagalopal, Krithika, Capitani, Melania, Cavounidis, Athena, Pires, Elisabete, Weidinger, Carl, McCullagh, James, Arkwright, Peter D., Haller, Wolfram, Siegmund, Britta, Peters, Lauren, Jostins, Luke, Travis, Simon P.L., Anderson, Carl A., Snapper, Scott, Klein, Christoph, Schadt, Eric, Zilbauer, Matthias, Xavier, Ramnik, Teichmann, Sarah, Muise, Aleixo M., Regev, Aviv, and Uhlig, Holm H.

Published
2022
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30. Valosin-containing protein-regulated endoplasmic reticulum stress causes NOD2-dependent inflammatory responses

Author

Maryam Ghalandary, Yue Li, Thomas Fröhlich, Thomas Magg, Yanshan Liu, Meino Rohlfs, Sebastian Hollizeck, Raffaele Conca, Tobias Schwerd, Holm H. Uhlig, Philip Bufler, Sibylle Koletzko, Aleixo M. Muise, Scott B. Snapper, Fabian Hauck, Christoph Klein, and Daniel Kotlarz

Subjects
Medicine, Science
Abstract

Abstract NOD2 polymorphisms may affect sensing of the bacterial muramyl dipeptide (MDP) and trigger perturbed inflammatory responses. Genetic screening of a patient with immunodeficiency and enteropathy revealed a rare homozygous missense mutation in the first CARD domain of NOD2 (ENST00000300589; c.160G > A, p.E54K). Biochemical assays confirmed impaired NOD2-dependent signaling and proinflammatory cytokine production in patient’s cells and heterologous cellular models with overexpression of the NOD2 mutant. Immunoprecipitation-coupled mass spectrometry unveiled the ATPase valosin-containing protein (VCP) as novel interaction partner of wildtype NOD2, while the binding to the NOD2 variant p.E54K was abrogated. Knockdown of VCP in coloncarcinoma cells led to impaired NF-κB activity and IL8 expression upon MDP stimulation. In contrast, tunicamycin-induced ER stress resulted in increased IL8, CXCL1, and CXCL2 production in cells with knockdown of VCP, while enhanced expression of these proinflammatory molecules was abolished upon knockout of NOD2. Taken together, these data suggest that VCP-mediated inflammatory responses upon ER stress are NOD2-dependent.

Published
2022
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31. Author Correction: Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

Author

Serra, Eva Gonçalves, Schwerd, Tobias, Moutsianas, Loukas, Cavounidis, Athena, Fachal, Laura, Pandey, Sumeet, Kammermeier, Jochen, Croft, Nicholas M., Posovszky, Carsten, Rodrigues, Astor, Russell, Richard K., Barakat, Farah, Auth, Marcus K. H., Heuschkel, Robert, Zilbauer, Matthias, Fyderek, Krzysztof, Braegger, Christian, Travis, Simon P., Satsangi, Jack, Parkes, Miles, Thapar, Nikhil, Ferry, Helen, Matte, Julie C., Gilmour, Kimberly C., Wedrychowicz, Andrzej, Sullivan, Peter, Moore, Carmel, Sambrook, Jennifer, Ouwehand, Willem, Roberts, David, Danesh, John, Baeumler, Toni A., Fulga, Tudor A., Carrami, Eli M, Ahmed, Ahmed, Wilson, Rachel, Barrett, Jeffrey C., Elkadri, Abdul, Griffiths, Anne M., Snapper, Scott B., Shah, Neil, Muise, Aleixo M., Wilson, David C., Uhlig, Holm H., and Anderson, Carl A.

Published
2022
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33. A conserved population of MHC II-restricted, innate-like, commensal-reactive T cells in the gut of humans and mice

Author

Hackstein, Carl-Philipp, Costigan, Dana, Drexhage, Linnea, Pearson, Claire, Bullers, Samuel, Ilott, Nicholas, Akther, Hossain Delowar, Gu, Yisu, FitzPatrick, Michael E. B., Harrison, Oliver J., Garner, Lucy C., Mann, Elizabeth H., Pandey, Sumeet, Friedrich, Matthias, Provine, Nicholas M., Uhlig, Holm H., Marchi, Emanuele, Powrie, Fiona, Klenerman, Paul, and Thornton, Emily E.

Published
2022
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34. Genomic Testing Identifies Monogenic Causes in Patients with Very Early-Onset Inflammatory Bowel Disease: A Multi-center Survey in an Iranian Cohort

Author

Eslamian, Golnaz, primary, Jamee, Mahnaz, additional, Momen, Tooba, additional, Rohani, Pejman, additional, Ebrahimi, Sarehossadat, additional, Mesdaghi, Mehrnaz, additional, Ghadimi, Soodeh, additional, Mansouri, Mahboubeh, additional, Mahdaviani, Seyed Alireza, additional, Sadeghi-shabestari, Mahnaz, additional, Fallahpour, Morteza, additional, Shamsian, Bibi Shahin, additional, Eslami, Narges, additional, Sharafian, Samin, additional, Dara, Naghi, additional, Nasri, Peiman, additional, Amini, Niloufar, additional, Enayat, Javad, additional, Fallahi, Mazdak, additional, Ghasemi Hashtrodi, Leila, additional, Shojaei, Mohammad, additional, Guevara Becerra, Martha, additional, Uhlig, Holm H, additional, and Chavoshzadeh, Zahra, additional

Published
2024
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37. IL-1-driven stromal–neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies

Author

Friedrich, Matthias, Pohin, Mathilde, Jackson, Matthew A., Korsunsky, Ilya, Bullers, Samuel J., Rue-Albrecht, Kevin, Christoforidou, Zoe, Sathananthan, Dharshan, Thomas, Tom, Ravindran, Rahul, Tandon, Ruchi, Peres, Raphael Sanches, Sharpe, Hannah, Wei, Kevin, Watts, Gerald F. M., Mann, Elizabeth H., Geremia, Alessandra, Attar, Moustafa, McCuaig, Sarah, Thomas, Lloyd, Collantes, Elena, Uhlig, Holm H., Sansom, Stephen N., Easton, Alistair, Raychaudhuri, Soumya, Travis, Simon P., and Powrie, Fiona M.

Published
2021
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39. The Childhood Acute Illness and Nutrition (CHAIN) network nested case-cohort study protocol: a multi-omics approach to understanding mortality among children in sub-Saharan Africa and South Asia [version 2; peer review: 2 approved]

Author

Albert Koulman, Kelsey Jones, James Berkley, Judd Walson, Eric Houpt, David S. Wishart, Christina L. Lancioni, Moses Ngari, Lei Xia, James M. Njunge, Abdoulaye Hama Diallo, Kirkby Tickell, Md. Amran Gazi, Abu Sadat Mohammad Sayeem Bin Shahid, Zaubina Kazi, Ali Saleem, Caroline Tigoi, Syed Ali, Emily Yoshioka, Ezekiel Mupere, Moses Mburu, Mohammod Jobayer Chisti, Bonface Gichuki, Narshion Ngao, Wilson Gumbi, Elisha Omer, Robert Bandsma, Benson Singa, Wieger Voskuijl, Tahmeed Ahmed, Alex Macharia, Thomas N. Williams, Anna Mitchel, Johnstone Makale, Joe Gogain, Jessica Williams, Rupasri Mandal, Nebojsa Janjic, Michael Routledge, Hang Wu, Camilo Espinosa, Yun Yun Gong, Jie Liu, Nima Aghaeepour, Hilary Browne, Trevor D. Lawley, Doreen Rwigi, Yan Shao, Timothy Kaburu, Kevin Kariuki, Lisa Gartner, and Holm H. Uhlig

Subjects
Case-Cohort, Mortality, Children, LMIC, Omics, Systems Biology, eng, Medicine
Abstract

Introduction: Many acutely ill children in low- and middle-income settings have a high risk of mortality both during and after hospitalisation despite guideline-based care. Understanding the biological mechanisms underpinning mortality may suggest optimal pathways to target for interventions to further reduce mortality. The Childhood Acute Illness and Nutrition (CHAIN) Network (www.chainnnetwork.org) Nested Case-Cohort Study (CNCC) aims to investigate biological mechanisms leading to inpatient and post-discharge mortality through an integrated multi-omic approach. Methods and analysis; The CNCC comprises a subset of participants from the CHAIN cohort (1278/3101 hospitalised participants, including 350 children who died and 658 survivors, and 270/1140 well community children of similar age and household location) from nine sites in six countries across sub-Saharan Africa and South Asia. Systemic proteome, metabolome, lipidome, lipopolysaccharides, haemoglobin variants, toxins, pathogens, intestinal microbiome and biomarkers of enteropathy will be determined. Computational systems biology analysis will include machine learning and multivariate predictive modelling with stacked generalization approaches accounting for the different characteristics of each biological modality. This systems approach is anticipated to yield mechanistic insights, show interactions and behaviours of the components of biological entities, and help develop interventions to reduce mortality among acutely ill children. Ethics and dissemination. The CHAIN Network cohort and CNCC was approved by institutional review boards of all partner sites. Results will be published in open access, peer reviewed scientific journals and presented to academic and policy stakeholders. Data will be made publicly available, including uploading to recognised omics databases. Trial registration NCT03208725.

Published
2022
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40. Cells of the human intestinal tract mapped across space and time

Author

Elmentaite, Rasa, Kumasaka, Natsuhiko, Roberts, Kenny, Fleming, Aaron, Dann, Emma, King, Hamish W., Kleshchevnikov, Vitalii, Dabrowska, Monika, Pritchard, Sophie, Bolt, Liam, Vieira, Sara F., Mamanova, Lira, Huang, Ni, Perrone, Francesca, Goh Kai’En, Issac, Lisgo, Steven N., Katan, Matilda, Leonard, Steven, Oliver, Thomas R. W., Hook, C. Elizabeth, Nayak, Komal, Campos, Lia S., Domínguez Conde, Cecilia, Stephenson, Emily, Engelbert, Justin, Botting, Rachel A., Polanski, Krzysztof, van Dongen, Stijn, Patel, Minal, Morgan, Michael D., Marioni, John C., Bayraktar, Omer Ali, Meyer, Kerstin B., He, Xiaoling, Barker, Roger A., Uhlig, Holm H., Mahbubani, Krishnaa T., Saeb-Parsy, Kourosh, Zilbauer, Matthias, Clatworthy, Menna R., Haniffa, Muzlifah, James, Kylie R., and Teichmann, Sarah A.

Published
2021
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41. Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel Disease

Author

Al-Kaabi, Saad R., Al-Mohannadi, Muneera J., Al Ejji, Khalid M., Yakoob, Rafie A., Abunahia, Nevin S.M., Mir, Fayaz A., Hamad Medical Corporation, Doha, Qatar, Uhlig, Holm H., Travis, Simon P.L., University of Oxford, Oxford, UK, Elawad, Mamoun, Akobeng, Anthony K., Ibrahim, Nazira A., Al-Mudahka, Fatma, Lo, Bernice, Sidra Medicine, Doha, Qatar, Al-Shaibi, Ahmad A., Abdel-Motal, Ussama M., Hubrack, Satanay Z., Bullock, Alex N., Al-Marri, Amna A., Agrebi, Nourhen, Al-Subaiey, Abdulrahman A., and Charles, Adrian K.

Published
2021
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44. Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice

Author

Wang, Lin, Aschenbrenner, Dominik, Zeng, Zhiyang, Cao, Xiya, Mayr, Daniel, Mehta, Meera, Capitani, Melania, Warner, Neil, Pan, Jie, Wang, Liren, Li, Qi, Zuo, Tao, Cohen-Kedar, Sarit, Lu, Jiawei, Ardy, Rico Chandra, Mulder, Daniel J., Dissanayake, Dilan, Peng, Kaiyue, Huang, Zhiheng, Li, Xiaoqin, Wang, Yuesheng, Wang, Xiaobing, Li, Shuchao, Bullers, Samuel, Gammage, Anís N., Warnatz, Klaus, Schiefer, Ana-Iris, Krivan, Gergely, Goda, Vera, Kahr, Walter H. A., Lemaire, Mathieu, Lu, Chien-Yi, Siddiqui, Iram, Surette, Michael G., Kotlarz, Daniel, Engelhardt, Karin R., Griffin, Helen R., Rottapel, Robert, Decaluwe, Hélène, Laxer, Ronald M., Proietti, Michele, Hambleton, Sophie, Elcombe, Suzanne, Guo, Cong-Hui, Grimbacher, Bodo, Dotan, Iris, Ng, Siew C., Freeman, Spencer A., Snapper, Scott B., Klein, Christoph, Boztug, Kaan, Huang, Ying, Li, Dali, Uhlig, Holm H., and Muise, Aleixo M.

Published
2021
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45. Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel DiseaseSummary

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, Simon P.L. Travis, Anthony K. Akobeng, and Fatma Al-Mudahka

Subjects
AGR2, MUC2, ER Stress, Intestinal Metaplasia, Goblet Cells, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

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.

Published
2021
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47. Cessation of exclusive breastfeeding and seasonality, but not small intestinal bacterial overgrowth, are associated with environmental enteric dysfunction: A birth cohort study amongst infants in rural Kenya

Author

Rosie J. Crane, Edward P.K. Parker, Simon Fleming, Agnes Gwela, Wilson Gumbi, Joyce M. Ngoi, Zaydah R. de Laurent, Emily Nyatichi, Moses Ngari, Juliana Wambua, Holm H. Uhlig, and James A. Berkley

Subjects
Environmental enteric dysfunction, Stunting, Small intestinal bacterial overgrowth, Infant feeding, Gut microbiota, Breastfeeding, Medicine (General), R5-920
Abstract

Summary: Background: Environmental Enteric Dysfunction (EED) is a chronic intestinal inflammatory disorder of unclear aetiology prevalent amongst children in low-income settings and associated with stunting. We aimed to characterise development of EED and its putative risk factors amongst rural Kenyan infants. Methods: In a birth cohort study in Junju, rural coastal Kenya, between August 2015 and January 2017, 100 infants were each followed for nine months. Breastfeeding status was recorded weekly and anthropometry monthly. Acute illnesses and antibiotics were captured by active and passive surveillance. Intestinal function and small intestinal bacterial overgrowth (SIBO) were assessed by monthly urinary lactulose mannitol (LM) and breath hydrogen tests. Faecal alpha-1-antitrypsin, myeloperoxidase and neopterin were measured as EED biomarkers, and microbiota composition assessed by 16S sequencing. Findings: Twenty nine of the 88 participants (33%) that underwent length measurement at nine months of age were stunted (length-for-age Z score

Published
2022
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48. UNC45A deficiency causes microvillus inclusion disease–like phenotype by impairing myosin VB–dependent apical trafficking

Author

Rémi Duclaux-Loras, Corinne Lebreton, Jérémy Berthelet, Fabienne Charbit-Henrion, Ophelie Nicolle, Céline Revenu de Courtils, Stephanie Waich, Taras Valovka, Anis Khiat, Marion Rabant, Caroline Racine, Ida Chiara Guerrera, Júlia Baptista, Maxime M. Mahe, Michael W. Hess, Béatrice Durel, Nathalie Lefort, Céline Banal, Mélanie Parisot, Cecile Talbotec, Florence Lacaille, Emmanuelle Ecochard-Dugelay, Arzu Meltem Demir, Georg F. Vogel, Laurence Faivre, Astor Rodrigues, Darren Fowler, Andreas R. Janecke, Thomas Müller, Lukas A. Huber, Fernando Rodrigues-Lima, Frank M. Ruemmele, Holm H. Uhlig, Filippo Del Bene, Grégoire Michaux, Nadine Cerf-Bensussan, and Marianna Parlato

Subjects
Gastroenterology, Medicine
Abstract

Variants in the UNC45A cochaperone have been recently associated with a syndrome combining diarrhea, cholestasis, deafness, and bone fragility. Yet the mechanism underlying intestinal failure in UNC45A deficiency remains unclear. Here, biallelic variants in UNC45A were identified by next-generation sequencing in 6 patients with congenital diarrhea. Corroborating in silico prediction, variants either abolished UNC45A expression or altered protein conformation. Myosin VB was identified by mass spectrometry as client of the UNC45A chaperone and was found misfolded in UNC45AKO Caco-2 cells. In keeping with impaired myosin VB function, UNC45AKO Caco-2 cells showed abnormal epithelial morphogenesis that was restored by full-length UNC45A, but not by mutant alleles. Patients and UNC45AKO 3D organoids displayed altered luminal development and microvillus inclusions, while 2D cultures revealed Rab11 and apical transporter mislocalization as well as sparse and disorganized microvilli. All those features resembled the subcellular abnormalities observed in duodenal biopsies from patients with microvillus inclusion disease. Finally, microvillus inclusions and shortened microvilli were evidenced in enterocytes from unc45a-deficient zebrafish. Taken together, our results provide evidence that UNC45A plays an essential role in epithelial morphogenesis through its cochaperone function of myosin VB and that UNC45A loss causes a variant of microvillus inclusion disease.

Published
2022
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