PUBLICATION
Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish
- Authors
- Patterson, V., Ullah, F., Bryant, L., Dong, L.I., Griffin, J.N., Sidhu, A., Saliganan, S., Blaile, M., Saenz, M.S., Smith, R., Ellingwood, S., Grange, D.K., Hu, X., Mireguli, M., Luo, Y., Shen, Y., Mulhern, M., Zackai, E., Ritter, A., Izumi, K., Hoefele, J., Wagner, M., Riedhammer, K.M., Seitz, B., Robin, N.H., Goodloe, D., Mignot, C., Keren, B., Cox, H., Jarvis, J., Hempel, M., Gibson, C.F., Tran Mau-Them, F., Vitobello, A., Bruel, A.L., Sorlin, A., Mehta, S., Raymond, F.L., Gilmore, K., Powell, B.C., Weck, K., Li, C., Vulto-van Silfhout, A.T., Giacomini, T., Mancardi, M.M., Accogli, A., Salpietro, V., Zara, F., Vora, N.L., Davis, E.E., Burdine, R.D., Bhoj, E.
- ID
- ZDB-PUB-230502-40
- Date
- 2023
- Source
- Science advances 9: eade0631eade0631 (Journal)
- Registered Authors
- Burdine, Rebecca
- Keywords
- none
- MeSH Terms
-
- Animals
- Humans
- Intracellular Signaling Peptides and Proteins
- Protein Serine-Threonine Kinases
- Signal Transduction*
- Zebrafish*
- PubMed
- 37126546 Full text @ Sci Adv
Citation
Patterson, V., Ullah, F., Bryant, L., Dong, L.I., Griffin, J.N., Sidhu, A., Saliganan, S., Blaile, M., Saenz, M.S., Smith, R., Ellingwood, S., Grange, D.K., Hu, X., Mireguli, M., Luo, Y., Shen, Y., Mulhern, M., Zackai, E., Ritter, A., Izumi, K., Hoefele, J., Wagner, M., Riedhammer, K.M., Seitz, B., Robin, N.H., Goodloe, D., Mignot, C., Keren, B., Cox, H., Jarvis, J., Hempel, M., Gibson, C.F., Tran Mau-Them, F., Vitobello, A., Bruel, A.L., Sorlin, A., Mehta, S., Raymond, F.L., Gilmore, K., Powell, B.C., Weck, K., Li, C., Vulto-van Silfhout, A.T., Giacomini, T., Mancardi, M.M., Accogli, A., Salpietro, V., Zara, F., Vora, N.L., Davis, E.E., Burdine, R.D., Bhoj, E. (2023) Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish. Science advances. 9:eade0631eade0631.
Abstract
We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4). MAP4K4 has been implicated in many signaling pathways including c-Jun N-terminal and RAS kinases and is currently under investigation as a druggable target for multiple disorders. Using several zebrafish models, we demonstrate that these human variants are either loss-of-function or dominant-negative alleles and show that decreasing Map4k4 activity causes developmental defects. Furthermore, MAP4K4 can restrain hyperactive RAS signaling in early embryonic stages. Together, our data demonstrate that MAP4K4 negatively regulates RAS signaling in the early embryo and that variants identified in affected humans abrogate its function, establishing MAP4K4 as a causal locus for individuals with syndromic neurodevelopmental differences.
Errata / Notes
This article is corrected by ZDB-PUB-231125-7.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping