PUBLICATION
Human ITGAV variants are associated with immune dysregulation, brain abnormalities, and colitis
- Authors
- 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., 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.
- ID
- ZDB-PUB-241114-22
- Date
- 2024
- Source
- The Journal of experimental medicine 221(12): (Journal)
- Registered Authors
- van Ham, Tjakko, Zhao, Mo
- Keywords
- none
- Datasets
- GEO:GSE248975
- MeSH Terms
-
- Colitis*/genetics
- Colitis*/immunology
- Colitis*/pathology
- Pedigree
- Zebrafish*/genetics
- Brain*/metabolism
- Brain*/pathology
- Signal Transduction/genetics
- Humans
- Female
- Transforming Growth Factor beta/genetics
- Transforming Growth Factor beta/metabolism
- Male
- Animals
- PubMed
- 39526957 Full text @ J. Exp. Med.
Citation
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., 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. (2024) Human ITGAV variants are associated with immune dysregulation, brain abnormalities, and colitis. The Journal of experimental medicine. 221(12):.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping