Human ITGAV variants are associated with immune dysregulation, brain abnormalities, and colitis.

Autor:	Ghasempour S; Cell Biology Program, Research Institute, Hospital for Sick Children , Toronto, Canada.; Department of Biochemistry, University of Toronto, Toronto, Canada., Warner N; Cell Biology Program, Research Institute, Hospital for Sick Children , Toronto, Canada., Guan R; Cell Biology Program, Research Institute, Hospital for Sick Children , Toronto, Canada., Rodari MM; Laboratory of Intestinal Immunity, Université Paris-Cité, Institut Imagine, INSERM U1163 , Paris, France., Ivanochko D; Program in Molecular Medicine, The Hospital for Sick Children Research Institute , Toronto, Canada., Whittaker Hawkins R; Cell Biology Program, Research Institute, Hospital for Sick Children , Toronto, Canada., Marwaha A; Division of Genetics, Department of Medical Genetics, University of Calgary, Alberta Children's Hospital, Calgary, Canada., Nowak JK; Laboratory of Intestinal Immunity, Université Paris-Cité, Institut Imagine, INSERM U1163 , Paris, France., Liang Y; Center for Computational Medicine, Research Institute, Hospital for Sick Children , Toronto, Canada., Mulder DJ; Department of Pediatrics, Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Canada., Stallard L; National Centre for Pediatric Gastroenterology, Children's Health Ireland , Dublin, Ireland., Li M; Center for Computational Medicine, Research Institute, Hospital for Sick Children , Toronto, Canada., Yu DD; Cell Biology Program, Research Institute, Hospital for Sick Children , Toronto, Canada., Pluthero FG; Department of Biochemistry, University of Toronto, Toronto, Canada., Batura V; Cell Biology Program, Research Institute, Hospital for Sick Children , Toronto, Canada., Zhao M; Genetics and Genome Biology, Research Institute, Hospital for Sick Children , Toronto, Canada., Siddiqui I; Division of Pathology, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada.; Laboratory Medicine and Pathobiology, University of Toronto , Toronto, Canada., Upton JEM; Division of Immunology and Allergy, The Hospital for Sick Children, Toronto, Canada.; Department of Paediatrics, University of Toronto, Toronto, Canada., Hulst JM; Department of Paediatrics, University of Toronto, Toronto, Canada.; Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, Toronto, Canada., Kahr WHA; Cell Biology Program, Research Institute, Hospital for Sick Children , Toronto, Canada.; Department of Biochemistry, University of Toronto, Toronto, Canada.; Department of Paediatrics, University of Toronto, Toronto, Canada., Mendoza-Londono R; Department of Paediatrics, University of Toronto, Toronto, Canada.; Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, Toronto, Canada., Charbit-Henrion F; Laboratory of Intestinal Immunity, Université Paris-Cité, Institut Imagine, INSERM U1163 , Paris, France.; Genomic Medicine for Rare Diseases, Necker-Enfants Malades Hospital , Paris, France., Hoefsloot LH; Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands., Khiat A; Laboratory of Intestinal Immunity, Université Paris-Cité, Institut Imagine, INSERM U1163 , Paris, France., Moreira D; Consulta de Imunodeficiências Primárias, Serviço de Pediatria, Centro Hospitalar Vila Nova de Gaia e Espinho , Vila Nova de Gaia, Portugal., Trindade E; Department of Pediatrics, Unit of Pediatric Gastroenterology, Hepatology and Nutrition, Centro Hospitalar Universitário de São João, Porto, Portugal., Espinheira MDC; Department of Pediatrics, Unit of Pediatric Gastroenterology, Hepatology and Nutrition, Centro Hospitalar Universitário de São João, Porto, Portugal., Pinto Pais I; Department of Pediatrics, Unit of Pediatric Gastroenterology, Hepatology and Nutrition, Centro Hospitalar Universitário de São João, Porto, Portugal., Weerts MJA; Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands., Douben H; Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands., Kotlarz D; Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.; German Center for Child and Adolescent Health, Munich Site , Munich, Germany.; Institute of Translational Genomics, Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg, Germany., Snapper SB; Division of Gastroenterology, Hepatology and Nutrition, Boston, Children's Hospital, Harvard Medical School, Boston, MA, USA.; Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA., Klein C; Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.; German Center for Child and Adolescent Health, Munich Site , Munich, Germany., Dowling JJ; Genetics and Genome Biology, Research Institute, Hospital for Sick Children , Toronto, Canada.; Department of Paediatrics, University of Toronto, Toronto, Canada., Julien JP; Program in Molecular Medicine, The Hospital for Sick Children Research Institute , Toronto, Canada., Joosten M; Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands., Cerf-Bensussan N; Laboratory of Intestinal Immunity, Université Paris-Cité, Institut Imagine, INSERM U1163 , Paris, France., Freeman SA; Cell Biology Program, Research Institute, Hospital for Sick Children , Toronto, Canada.; Department of Biochemistry, University of Toronto, Toronto, Canada., Parlato M; Laboratory of Intestinal Immunity, Université Paris-Cité, Institut Imagine, INSERM U1163 , Paris, France., van Ham TJ; Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands., Muise AM; Cell Biology Program, Research Institute, Hospital for Sick Children , Toronto, Canada.; Department of Biochemistry, University of Toronto, Toronto, Canada.; Department of Paediatrics, University of Toronto, Toronto, Canada.; Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, Toronto, Canada.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2024 Dec 02; Vol. 221 (12). Date of Electronic Publication: 2024 Nov 11.
DOI:	10.1084/jem.20240546
Abstrakt:	Integrin heterodimers containing an Integrin alpha V subunit are essential for development and play critical roles in cell adhesion and signaling. We identified biallelic variants in the gene coding for Integrin alpha V (ITGAV) in three independent families (two patients and four fetuses) that either caused abnormal mRNA and the loss of functional protein or caused mistargeting of the integrin. This led to eye and brain abnormalities, inflammatory bowel disease, immune dysregulation, and other developmental issues. Mechanistically, the reduction of functional Integrin αV resulted in the dysregulation of several pathways including TGF-β-dependent signaling and αVβ3-regulated immune signaling. These effects were confirmed using immunostaining, RNA sequencing, and functional studies in patient-derived cells. The genetic deletion of itgav in zebrafish recapitulated patient phenotypes including retinal and brain defects and the loss of microglia in early development as well as colitis in juvenile zebrafish with reduced SMAD3 expression and transcriptional regulation. Taken together, the ITGAV variants identified in this report caused a previously unknown human disease characterized by brain and developmental defects in the case of complete loss-of-function and atopy, neurodevelopmental defects, and colitis in cases of incomplete loss-of-function. (© 2024 Ghasempour et al.)
Databáze:	MEDLINE
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