1. Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis
- Author
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Claudio Romano, Paola De Angelis, Jie Pan, Marc Bras, Anne M. Griffiths, Karoline Fiedler, Paola Francalanci, Marianna Parlato, Nadine Cerf-Bensussan, Mohammed Zarhrate, Frank M. Ruemmele, Eileen Crowley, Aleixo M. Muise, Rémi Duclaux-Loras, Bernadette Bègue, Fabienne Charbit-Henrion, Nicolas Guegan, Julie Bruneau, Sabine Rakotobe, Nathalie Kapel, Marie‐Helene Le Du, Neil Warner, SERRE, Marie-Claude, Laboratory of Intestinal Immunity (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), GENIUS Group, Service de Gastroentérologie, d'hépatologie et nutrition pédiatrique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Hospital for sick children [Toronto] (SickKids), University of Messina, Department of Pathology, University of Alabama at Birmingham [ Birmingham] (UAB), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Children's Hospital Bambino Gesù IRCCS [Rome], Université Paris Descartes - Paris 5 (UPD5), Service de pathologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Plateforme de bioinformatique (UNIV Paris Descartes), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Toronto, and Université Sorbonne Paris Cité (USPC)
- Subjects
0301 basic medicine ,Agonist ,Medicine (General) ,medicine.drug_class ,[SDV]Life Sciences [q-bio] ,Biology ,QH426-470 ,GPI-Linked Proteins ,Inflammatory bowel disease ,inflammatory bowel diseases ,intestinal phosphatase alkaline ,Lipid A ,03 medical and health sciences ,INTGEN ,R5-920 ,medicine ,Genetics ,Homeostasis ,Humans ,Receptor ,Loss function ,Research Articles ,HEK 293 cells ,medicine.disease ,Alkaline Phosphatase ,3. Good health ,Intestines ,[SDV] Life Sciences [q-bio] ,030104 developmental biology ,HEK293 Cells ,Metabolism ,inflammatory bowel diseases, intestinal phosphatase alkaline, monogenic disease, Molecular Medicine ,Immunology ,Mutation ,Alkaline phosphatase ,monogenic disease ,Molecular Medicine ,Heterologous expression ,Genetics, Gene Therapy & Genetic Disease ,Digestive System ,B3S ,Signal Transduction ,Research Article - Abstract
International audience; Herein, we report the first identification of biallelic-inherited mutations inALPIas a Mendelian cause of inflammatory bowel disease in two unrelated patients.ALPIencodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that allALPImutations were loss of function.ALPImutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients' biopsies, and ALPI activity was undetectable in ALPI-deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host-microbiota interactions and restraining host inflammatory responses. These results indicate thatALPImutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders.
- Published
- 2018
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