PuSH - Publikationsserver des Helmholtz Zentrums München

Export: TXT Text RIS Endnote (RIS) BIB BibTeX
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 Hybrid
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.
Impact Factor
Scopus SNIP
Altmetric
12.800
0.000
Tags
Anmerkungen
Besondere Publikation
Auf Hompepage verbergern

Zusatzinfos bearbeiten
Eigene Tags bearbeiten
Privat
Eigene Anmerkung bearbeiten
Privat
Auf Publikationslisten für
Homepage nicht anzeigen
Als besondere Publikation
markieren
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Sprache englisch
Veröffentlichungsjahr 2024
HGF-Berichtsjahr 2024
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
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Translational Genomics (ITG)
POF Topic(s) 30205 - Bioengineering and Digital Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-506700-001
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
DOI 10.1084/jem.20240546
Scopus ID 85209477154
PubMed ID 39526957
Erfassungsdatum 2024-11-20
[➜Korrektur melden]