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

Victoria Patterson, Princeton University, Princeton, NJ 08544, USA.
Farid Ullah, 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.
Laura Bryant, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
John N. Griffin, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK.
Alpa Sidhu, The Stead Family Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA.
Sheila Saliganan, Ambry Genetics, 1 Enterprise, Aliso Viejo, CA 92656, USA.
Mackenzie Blaile, University of Colorado Anschutz Medical Campus, 13001 E 17th Pl, Aurora, CO 80045, USA.
Margarita S. Saenz, University of Colorado Anschutz Medical Campus, 13001 E 17th Pl, Aurora, CO 80045, USA.
Rosemarie Smith, Maine Medical Center, 22 Bramhall St, Portland, ME 04102, USA.
Sara Ellingwood, Maine Medical Center, 22 Bramhall St, Portland, ME 04102, USA.
Dorothy K. Grange, St. Louis Children's Hospital, Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110, USA.
Xuyun Hu, 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.
Maimaiti Mireguli, First Affiliated Hospital of Xinjiang Medical University, Department of Pediatrics, Xinjiang Uygur Autonomous Region, China.
Yanfei Luo, First Affiliated Hospital of Xinjiang Medical University, Department of Pediatrics, Xinjiang Uygur Autonomous Region, China.
Yiping Shen, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Maureen Mulhern, Columbia University Irving Medical Center, 630 W. 168th St, New York, NY 10032, USA.
Elaine Zackai, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Alyssa Ritter, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Kosaki Izumi, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Julia Hoefele, Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
Matias Wagner, Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
Korbinian M. Riedhammer, Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
Barbara Seitz, KfH Pediatric Kidney Center Munich, Munich, Germany.
Nathaniel H. Robin, University of Alabama at Birmingham, 1720 University Blvd, Birmingham, AL 35233, USA.
Dana Goodloe, University of Alabama at Birmingham, 1720 University Blvd, Birmingham, AL 35233, USA.
Cyril Mignot, APHP-Sorbonne Université, GH Pitié-Salpêtrière, Paris, France.
Boris Keren, Clinical Genetics Unit, Birmingham Women's and Children's NHS Foundation Trust, Mindelsohn Way, Birmingham B15 2TG, UK.
Helen Cox, Clinical Genetics Unit, Birmingham Women's and Children's NHS Foundation Trust, Mindelsohn Way, Birmingham B15 2TG, UK.
Joanna Jarvis, Clinical Genetics Unit, Birmingham Women's and Children's NHS Foundation Trust, Mindelsohn Way, Birmingham B15 2TG, UK.
Maja Hempel, University Hospital Hamburg-Eppendorf, Martinistraße 52, 20251 Hamburg, Germany.
Cynthia Forster Gibson, Trillium Health Partners, Mississauga, ON L5B 2V2, Canada.
Frederic Tran Mau-Them, University of Bourgogne, Dijon, France.

Abstract

We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in (). 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 as a causal locus for individuals with syndromic neurodevelopmental differences.