PuSH - Publication Server of Helmholtz Zentrum München: Human <em>ITGAV</em> variants are associated with immune dysregulation, brain abnormalities, and colitis.

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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)

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	Open Access Gold (Paid Option)

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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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

ISSN (print) / ISBN 0022-1007

e-ISSN 1540-9538

Journal Journal of Experimental Medicine

Quellenangaben Volume: 221, Issue: 12, Article Number: e20240546

Publisher Rockefeller University Press

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Translational Genomics (ITG)

Grants 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