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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)
Verlagsversion 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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Kinase 4; Inhibition; Mutations; Variants; Association; Expression; Fgfr-1; Growth; Noonan; Cells
Sprache englisch
Veröffentlichungsjahr 2023
HGF-Berichtsjahr 2023
ISSN (print) / ISBN 2375-2548
e-ISSN 2375-2548
Zeitschrift Science Advances
Quellenangaben Band: 9, Heft: 17, Seiten: , Artikelnummer: eade0631 Supplement: ,
Verlag American Association for the Advancement of Science (AAAS)
Verlagsort Washington, DC [u.a.]
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
POF Topic(s) 30205 - Bioengineering and Digital Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-503200-001
Förderungen 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
DOI 10.1126/sciadv.ade0631
WOS ID 001263608900002
WOS ID 000989268500002
Scopus ID 85158069250
PubMed ID 37126546
Erfassungsdatum 2023-10-06
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