Human <i>ITGAV</i> variants are associated with immune dysregulation, brain abnormalities, and colitis
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.
Authors
- Walter H.A. Kahr (ORCID: https://orcid.org/0000-0002-2832-7158)
- Marianna Parlato (ORCID: https://orcid.org/0000-0002-8750-082X)
- Marieke Joosten (ORCID: https://orcid.org/0000-0002-4443-4690)
- Nadine Cerf–Bensussan (ORCID: https://orcid.org/0000-0003-0665-1245)
- Isabel Pinto Pais (ORCID: https://orcid.org/0000-0002-4953-5992)
- Jan Krzysztof Nowak (ORCID: https://orcid.org/0000-0003-0953-2188)
- Roberto Mendoza‐Londono (ORCID: https://orcid.org/0000-0003-3542-8106)
- Fred G. Pluthero (ORCID: https://orcid.org/0000-0002-0451-5840)
- Tjakko J. van Ham (ORCID: https://orcid.org/0000-0002-2175-8713)
- Jessie M. Hulst (ORCID: https://orcid.org/0000-0002-4899-7343)
- Neil Warner (ORCID: https://orcid.org/0000-0002-9207-5979)
- Danton Ivanochko (ORCID: https://orcid.org/0000-0002-2826-8100)
- Sina Ghasempour (ORCID: https://orcid.org/0000-0002-5882-1536)
- James J. Dowling (ORCID: https://orcid.org/0000-0002-3984-4169)
- Aleixo M. Muise (ORCID: https://orcid.org/0000-0001-9624-3346)
- Spencer A. Freeman (ORCID: https://orcid.org/0000-0003-3455-3714)
- Marco M. Rodari (ORCID: https://orcid.org/0000-0001-9590-7884)
- Daniel Kotlarz (ORCID: https://orcid.org/0000-0002-4576-6769)
- Julia Upton (ORCID: https://orcid.org/0000-0001-5320-4232)
- Scott B. Snapper (ORCID: https://orcid.org/0000-0003-0267-4247)
- Maria do Céu Espinheira (ORCID: https://orcid.org/0000-0001-5494-6764)
- Jean‐Philippe Julien (ORCID: https://orcid.org/0000-0001-7602-3995)
- Iram Siddiqui (ORCID: https://orcid.org/0000-0003-4237-8207)
- Daniel J. Mulder (ORCID: https://orcid.org/0000-0003-2974-855X)
- Lorraine Stallard (ORCID: https://orcid.org/0000-0002-1280-6525)
- Daoqi Yu (ORCID: https://orcid.org/0000-0002-0860-7291)
- Mo Zhao (ORCID: https://orcid.org/0000-0002-3665-3738)
- Fabienne Charbit‐Henrion (ORCID: https://orcid.org/0000-0003-4615-3953)
- Vritika Batura
- Yijing Liang (ORCID: https://orcid.org/0009-0005-8010-5308)
- Ashish Marwaha (ORCID: https://orcid.org/0000-0003-1234-0224)
- Anis Khiat
- Ryder Whittaker Hawkins (ORCID: https://orcid.org/0000-0002-4018-5236)
- Eunice Trindade (ORCID: https://orcid.org/0000-0001-7034-3541)
- Michael Li (ORCID: https://orcid.org/0009-0006-2998-4201)
- Rui Guan (ORCID: https://orcid.org/0000-0002-4450-2817)
- Christoph A. Klein (ORCID: https://orcid.org/0000-0003-0956-0445)
- D. A. A. MOREIRA (ORCID: https://orcid.org/0009-0001-0531-723X)
- Lies H. Hoefsloot (ORCID: https://orcid.org/0009-0000-3444-9955)
- Hannie Douben
- Marjolein J.A. Weerts
Institutions
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Harvard University (US)
- Inserm (FR)
- University of Calgary (CA)
- University of Toronto (CA)
- Queen's University (CA)
- Université Paris Cité (FR)
- Great Ormond Street Hospital (GB)
- Hospital for Sick Children (CA)
- Erasmus MC (NL)
- Alberta Children's Hospital (CA)
- Helmholtz Zentrum München (DE)
- Hospital de São João (PT)
- German Center for Pediatric and Adolescent Rheumatology (DE)
- Institut Necker Enfants Malades (FR)
- SickKids Foundation (CA)
- Centro Hospitalar de Vila Nova de Gaia (PT)
- University College London (GB)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2024-11-11
- DOI
- https://doi.org/10.1084/jem.20240546
- Citations
- 6
- Primary Topic
- Immunodeficiency and Autoimmune Disorders
- Type
- article
- Field-Weighted Citation Impact
- 1.44
Funders
- Leona M. and Harry B. Helmsley Charitable Trust
- Canadian Institute for Advanced Research
- Genome Canada
- Ontario Research Foundation
- Ontario Genomics
- Government of Ontario
- Ontario Genomics Institute
- Canada Foundation for Innovation
- Genome British Columbia
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Canada Research Chairs
- Fondation pour la Recherche Médicale
- Narodowe Centrum Nauki
- Hospital for Sick Children
- Genome Alberta
- Fondation Princesse Grace de Monaco
- National Institutes of Health
- Canadian Institutes of Health Research