Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish-Reference-Cited by-同舟云学术

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

Published:2023-04-28 Issue:17 Volume:9 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Patterson Victoria¹²^ORCID,Ullah Farid³^ORCID,Bryant Laura⁴^ORCID,Li Dong⁵,Griffin John N.⁶,Sidhu Alpa⁷^ORCID,Saliganan Sheila⁸,Blaile Mackenzie⁹,Saenz Margarita S.⁹^ORCID,Smith Rosemarie¹⁰,Ellingwood Sara¹⁰,Grange Dorothy K.¹¹^ORCID,Hu Xuyun¹²^ORCID,Mireguli Maimaiti¹³,Luo Yanfei¹³,Shen Yiping¹⁴¹⁵^ORCID,Mulhern Maureen¹⁶^ORCID,Zackai Elaine⁴,Ritter Alyssa⁴^ORCID,Izumi Kosuke⁴,Hoefele Julia¹⁷^ORCID,Wagner Matias¹⁷¹⁸¹⁹^ORCID,Riedhammer Korbinian M.¹⁷²⁰^ORCID,Seitz Barbara²¹,Robin Nathaniel H.²²^ORCID,Goodloe Dana²²^ORCID,Mignot Cyril²³,Keren Boris²⁴^ORCID,Cox Helen²⁴,Jarvis Joanna²⁴,Hempel Maja²⁵,Gibson Cynthia Forster²⁶,Tran Mau-Them Frederic²⁷^ORCID,Vitobello Antonio²⁸²⁹^ORCID,Bruel Ange-Line²⁷,Sorlin Arthur²⁷,Mehta Sarju³⁰^ORCID,Raymond F. Lucy³¹,Gilmore Kelly³²^ORCID,Powell Bradford C.³³^ORCID,Weck Karen³⁴^ORCID,Li Chumei³⁵,Vulto-van Silfhout Anneke T.³⁶,Giacomini Thea³⁷,Mancardi Maria Margherita³⁸,Accogli Andrea³⁹⁴⁰,Salpietro Vincenzo⁴¹,Zara Federico⁴¹,Vora Neeta L.³²^ORCID,Davis Erica E.³^ORCID,Burdine Rebecca D.¹^ORCID,Bhoj Elizabeth⁴^ORCID

Affiliation:

1. Princeton University, Princeton, NJ 08544, USA.

2. Department of Biology, University of York, York, UK.

3. Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago, Departments of Pediatrics and Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

4. Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.

5. Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA.

6. University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK.

7. The Stead Family Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA.

8. Ambry Genetics, 1 Enterprise, Aliso Viejo, CA 92656, USA.

9. University of Colorado Anschutz Medical Campus, 13001 E 17th Pl, Aurora, CO 80045, USA.

10. Maine Medical Center, 22 Bramhall St, Portland, ME 04102, USA.

11. St. Louis Children’s Hospital, Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110, USA.

12. Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Genetics and Birth Defects Control Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China.

13. First Affiliated Hospital of Xinjiang Medical University, Department of Pediatrics, Xinjiang Uygur Autonomous Region, China.

14. Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.

15. Maternal and Child Care Hospital of Guangxi Zhuang Autonomous Region, Guangxi, Nanning, China.

16. Columbia University Irving Medical Center, 630 W. 168th St, New York, NY 10032, USA.

17. Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.

18. Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany.

19. Department of Pediatrics, Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, University Hospital of Munich, Ludwig Maximilians University, Munich, Germany.

20. Department of Nephrology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.

21. KfH Pediatric Kidney Center Munich, Munich, Germany.

22. University of Alabama at Birmingham, 1720 University Blvd, Birmingham, AL 35233, USA.

23. APHP-Sorbonne Université, GH Pitié-Salpêtrière, Paris, France.

24. Clinical Genetics Unit, Birmingham Women’s and Children’s NHS Foundation Trust, Mindelsohn Way, Birmingham B15 2TG, UK.

25. University Hospital Hamburg-Eppendorf, Martinistraße 52, 20251 Hamburg, Germany.

26. Trillium Health Partners, Mississauga, ON L5B 2V2, Canada.

27. University of Bourgogne, Dijon, France.

28. UMR1231 GAD, Inserm, Université Bourgogne-Franche-Comté, Dijon, France.

29. Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.

30. Addenbrooke’s Hospital, Cambridge, UK.

31. University of Cambridge, Cambridge, UK.

32. Department of Ob/Gyn, Division of Maternal-Fetal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

33. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

34. Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

35. McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.

36. Radboudumc Nijmegen, 6500 HB Nijmegen, Netherlands.

37. Unit of Child Neuropsychiatry, University of Genova, EpiCARE Network, IRCCS Istituto Giannina Gaslini, Genova, Italy.

38. Unit of Child Neuropsychiatry, EpiCARE Network, IRCCS Istituto Giannina Gaslini, Genova, Italy.

39. Division of Medical Genetics, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada.

40. Department of Human Genetics, McGill University, Montreal, QC, Canada.

41. Department of Biotechnological and Applied Clinical Science, University of L’Aquila, 67100 L’Aquila, Italy.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/sciadv.ade0631

Reference52 articles.

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