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Ghasempour, S.* ; Warner, N.* ; Guan, R.* ; Rodari, M.M.* ; Ivanochko, D.* ; Whittaker Hawkins, R.* ; Marwaha, A.* ; Nowak, J.K.* ; Liang, Y.* ; Mulder, D.J.* ; Stallard, L.* ; Li, M.* ; Yu, D.D.* ; Pluthero, F.G.* ; Batura, V.* ; Zhao, M.* ; Siddiqui, I.* ; Upton, J.E.M.* ; Hulst, J.M.* ; Kahr, W.H.A.* ; Mendoza-Londono, R.* ; Charbit-Henrion, F.* ; Hoefsloot, L.H.* ; Khiat, A.* ; Moreira, D.* ; Trindade, E.* ; Espinheira, M.D.C.* ; Pinto Pais, I.* ; Weerts, M.J.A.* ; Douben, H.* ; Kotlarz, D.M. ; Snapper, S.B.* ; Klein, C.* ; Dowling, J.J.* ; Julien, J.P.* ; Joosten, M.* ; Cerf-Bensussan, N.* ; Freeman, S.A.* ; Parlato, M.* ; van Ham, T.J.* ; Muise, A.M.*

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

J. Exp. Med. 221:e20240546 (2024)
Postprint DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
ISSN (print) / ISBN 0022-1007
e-ISSN 1540-9538
Zeitschrift Journal of Experimental Medicine
Quellenangaben Band: 221, Heft: 12, Seiten: , Artikelnummer: e20240546 Supplement: ,
Verlag Rockefeller University Press
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Translational Genomics (ITG)
Förderungen Lassonde Family Precision IBD Initiative
Canadian Institute for Advanced Research
Canada Research Chair Program
Canada Foundation for Innovation
Ontario Research Foundation
Institut National de la Santé et de la Recherche Médicale
Fondation Princesse Grace de Monaco
Leona M. and Harry B. Helmsley Charitable Trust
CIHR Foundation Grant
Government of Ontario
Hospital for Sick Children