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Patterson, V.* ; Ullah, F.* ; Bryant, L.* ; 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.* ; Bhoj, E.*

Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish.

Sci. Adv. 9:eade0631 (2023)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Kinase 4; Inhibition; Mutations; Variants; Association; Expression; Fgfr-1; Growth; Noonan; Cells
ISSN (print) / ISBN 2375-2548
e-ISSN 2375-2548
Journal Science Advances
Quellenangaben Volume: 9, Issue: 17, Pages: , Article Number: eade0631 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Publishing Place Washington, DC [u.a.]
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health
New Jersey Health Foundation Inc.
Duke/UNC CTSA Consortium Collaborative Translational Research Grant
National Human Genome Research Institute
National Institute of Mental Health
National Center for Advancing Translational Sciences
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute of General Medical Sciences
National Institute of Child Health and Human Development