Journal article
Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish
Science advances, Vol.9(17), eade0631
04/26/2023
DOI: 10.1126/sciadv.ade0631
PMCID: PMC10132768
PMID: 37126546
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.
MAP4K4 variants abrogate its negative regulation of RAS signaling, causing neurodevelopmental differences in 21 families.
Details
- Title: Subtitle
- Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish
- Creators
- Victoria Patterson - Princeton UniversityFarid Ullah - Lurie Children's HospitalLaura Bryant - Children's Hospital of PhiladelphiaJohn N. Griffin - University of East AngliaAlpa Sidhu - University of IowaSheila Saliganan - Ambry Genetics (United States)Mackenzie Blaile - University of Colorado Anschutz Medical CampusMargarita S. Saenz - University of Colorado Anschutz Medical CampusRosemarie Smith - Maine Medical CenterSara Ellingwood - Maine Medical CenterDorothy K. Grange - St. Louis Children's HospitalXuyun Hu - Beijing Children’s HospitalMaimaiti Mireguli - First Affiliated Hospital of Xinjiang Medical UniversityYanfei Luo - First Affiliated Hospital of Xinjiang Medical UniversityYiping Shen - Guangxi Maternal and Child Health HospitalMaureen Mulhern - Columbia University Irving Medical CenterElaine Zackai - Children's Hospital of PhiladelphiaAlyssa Ritter - Children's Hospital of PhiladelphiaKosaki Izumi - Children's Hospital of PhiladelphiaJulia Hoefele - TUM KlinikumMatias Wagner - TUM KlinikumKorbinian M. Riedhammer - TUM KlinikumBarbara Seitz - KfH Pediatric Kidney Center Munich, Munich, Germany.Nathaniel H. Robin - University of Alabama at BirminghamDana Goodloe - University of Alabama at BirminghamCyril Mignot - Université Paris CitéBoris Keren - Birmingham Women’s and Children’s NHS Foundation TrustHelen Cox - Birmingham Women’s and Children’s NHS Foundation TrustJoanna Jarvis - Birmingham Women’s and Children’s NHS Foundation TrustMaja Hempel - Eppendorf (Germany)Cynthia Forster Gibson - Trillium Health CentreFrederic Tran Mau-Them - University of Bourgogne, Dijon, FranceAntonio Vitobello - Université Bourgogne Franche-ComtéAnge-Line Bruel - Université de BourgogneArthur Sorlin - Université de BourgogneSarju Mehta - Addenbrooke's HospitalF. Lucy Raymond - University of CambridgeKelly Gilmore - University of North Carolina at Chapel HillBradford C. Powell - University of North Carolina at Chapel HillKaren Weck - University of North Carolina at Chapel HillChumei Li - McMaster UniversityAnneke T. Vulto-van Silfhout - Radboudumc Nijmegen, 6500 HB Nijmegen, NetherlandsThea Giacomini - Istituto Giannina GasliniMaria Margherita Mancardi - Istituto Giannina GasliniAndrea Accogli - McGill University Health CentreVincenzo Salpietro - University of L'AquilaFederico Zara - University of L'AquilaNeeta L. Vora - University of North Carolina at Chapel HillErica E. Davis - Lurie Children's HospitalRebecca Burdine - Princeton UniversityElizabeth Bhoj - Children's Hospital of Philadelphia
- Resource Type
- Journal article
- Publication Details
- Science advances, Vol.9(17), eade0631
- DOI
- 10.1126/sciadv.ade0631
- PMID
- 37126546
- PMCID
- PMC10132768
- NLM abbreviation
- Sci Adv
- eISSN
- 2375-2548
- Publisher
- American Association for the Advancement of Science
- Grant note
- R01GM086537 / ; R01HD105868 / ; DUR41703-UL1TR002553 / ; R03HD092694 / ; U01HG006487 / ; K23HD088742 / ; R01HD055651 / ; R01MH106826 / ; R01AR071486 / ; R21TR002770 / ;
- Alternative title
- MAP4K4 variants cause congenital anomalies
- Language
- English
- Date published
- 04/26/2023
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984399499502771
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