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Journal Articles Science Advances Year : 2023

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

Victoria Patterson
Farid Ullah
Laura Bryant
John N Griffin
  • Function : Author
Alpa Sidhu
Sheila Saliganan
  • Function : Author
Mackenzie Blaile
  • Function : Author
Margarita S Saenz
Rosemarie Smith
  • Function : Author
Sara Ellingwood
  • Function : Author
Dorothy K Grange
Xuyun Hu
Maimaiti Mireguli
  • Function : Author
Yanfei Luo
  • Function : Author
Yiping Shen
Maureen Mulhern
Elaine Zackai
  • Function : Author
Alyssa Ritter
Kosaki Izumi
  • Function : Author
Julia Hoefele
Matias Wagner
Korbinian M Riedhammer
Barbara Seitz
  • Function : Author
Nathaniel H Robin
Dana Goodloe
Boris Keren
Helen Cox
  • Function : Author
Joanna Jarvis
  • Function : Author
Maja Hempel
  • Function : Author
Cynthia Forster Gibson
  • Function : Author
Frederic Tran Mau-Them
Antonio Vitobello
Ange-Line Bruel
  • Function : Author
Arthur Sorlin
  • Function : Author
Sarju Mehta
F. Lucy Raymond
  • Function : Author
Kelly Gilmore
Bradford C Powell
Karen Weck
Chumei Li
  • Function : Author
Anneke T Vulto-van Silfhout
  • Function : Author
Thea Giacomini
  • Function : Author
Maria Margherita Mancardi
  • Function : Author
Andrea Accogli
  • Function : Author
Vincenzo Salpietro
  • Function : Author
Federico Zara
  • Function : Author
Neeta L Vora
Erica E Davis
Rebecca Burdine
Elizabeth Bhoj
Dong Li
  • Function : Author
Kosuke Izumi
  • Function : Author

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.
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hal-04584665 , version 1 (23-05-2024)

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Victoria Patterson, Farid Ullah, Laura Bryant, John N Griffin, Alpa Sidhu, et al.. Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish. Science Advances , 2023, 9 (17), pp.eade0631. ⟨10.1126/sciadv.ade0631⟩. ⟨hal-04584665⟩
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