A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction

Joanne M Hildebrand1,2, Maria Kauppi3,4, Ian J Majewski3,4, Zikou Liu3,4, Allison J Cox5, Sanae Miyake6, Emma J Petrie3,4, Michael A Silk7,8, Zhixiu Li9, Maria C Tanzer3,4,10, Gabriela Brumatti3,4, Samuel N Young3,4, Cathrine Hall3,4, Sarah E Garnish3,4, Jason Corbin3,4, Michael D Stutz3,4,11, Ladina Di Rago3,4, Pradnya Gangatirkar3,4, Emma C Josefsson3,4, Kristin Rigbye3,4,12, Holly Anderton3,4, James A Rickard3,4,13, Anne Tripaydonis3,4,13, Julie Sheridan3,4, Thomas S Scerri3,4, Victoria E Jackson3,4, Peter E Czabotar3,4, Jian-Guo Zhang3,4, Leila Varghese3,4,14, Cody C Allison3,4, Marc Pellegrini3,4, Gillian M Tannahill3,4,15, Esme C Hatchell3,4, Tracy A Willson3,4, Dina Stockwell3,4, Carolyn A de Graaf3,4, Janelle Collinge3,4, Adrienne Hilton3, Natasha Silke3,4, Sukhdeep K Spall3,4, Diep Chau3,4,16, Vicki Athanasopoulos17,18, Donald Metcalf3,4, Ronald M Laxer19, Alexander G Bassuk5,20, Benjamin W Darbro5, Maria A Fiatarone Singh21, Nicole Vlahovich22, David Hughes22, Maria Kozlovskaia22,23, David B Ascher7,8, Klaus Warnatz24,25, Nils Venhoff24, Jens Thiel24, Christine Biben3,4, Stefan Blum26, John Reveille27, Michael S Hildebrand28,29, Carola G Vinuesa17,18, Pamela McCombe30, Matthew A Brown9,31, Benjamin T Kile3,4,32, Catriona McLean33, Melanie Bahlo3,4, Seth L Masters3,4, Hiroyasu Nakano6, Polly J Ferguson5, James M Murphy3,4, Warren S Alexander34,35, John Silke36,37

  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. jhildebrand@wehi.edu.au.
  2. Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia. jhildebrand@wehi.edu.au.
  3. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  4. Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  5. Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
  6. Department of Biochemistry, Toho University School of Medicine, Ota-ku, Tokyo, 143-8540, Japan.
  7. Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Melbourne, VIC, 3052, Australia.
  8. Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
  9. Translational Genomics Group, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT) at Translational Research Institute, Brisbane, Australia.
  10. Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, 82152, Germany.
  11. Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, 97006, USA.
  12. Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, 3052, Australia.
  13. The Royal Melbourne Hospital, Melbourne, VIC, 3050, Australia.
  14. Ludwig Institute for Cancer Research and de Duve Institute, Brussels, Belgium.
  15. GSK Medicines Research Centre, Stevenage, UK.
  16. CSL Limited, Parkville, VIC, 3052, Australia.
  17. Department of Immunology and Infectious Disease and Centre for Personalised Immunology (NHMRC Centre for Research Excellence), John Curtin School of Medical Research, Australian National University, Canberra, Australia.
  18. Centre for Personalised Immunology (CACPI), Shanghai Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.
  19. Division of Rheumatology, The Hospital for Sick Children and the University of Toronto, Toronto, ON, Canada.
  20. Department of Neurology, University of Iowa Carver College of Medicine and the Iowa Neuroscience Institute, Iowa City, IA, USA.
  21. Faculty of Health Sciences and Sydney Medical School, University of Sydney, Sydney, Australia.
  22. Department of Sports Medicine, Australian Institute of Sport, Bruce, ACT, Australia.
  23. Faculty of Health, University of Canberra, Canberra, Australia.
  24. Department of Internal Medicine, Clinic for Rheumatology and Clinical Immunology, Medical Center -University of Freiburg, Faculty of Medicine, Freiburg, 79106, Germany.
  25. Center for Chronic Immunodeficiency, Medical Center -University of Freiburg, Faculty of Medicine, Freiburg, Germany.
  26. Princess Alexandra Hospital, Brisbane, QLD, Australia.
  27. Memorial Hermann Texas Medical Centre, Houston, TX, USA.
  28. Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, 3084, Australia.
  29. Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC, 3052, Australia.
  30. The University of Queensland, UQ Centre for Clinical Research, Royal Brisbane & Women's Hospital, Brisbane, Australia.
  31. NIHR Biomedical Research Centre, Kings College, London, UK.
  32. Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia.
  33. Department of Anatomical Pathology, The Alfred Hospital, Prahran, VIC, 3181, Australia.
  34. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. alexandw@wehi.edu.au.
  35. Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia. alexandw@wehi.edu.au.
  36. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. silke@wehi.edu.au.
  37. Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia. silke@wehi.edu.au.

Abstract

MLKL is the essential effector of necroptosis, a form of programmed lytic cell death. We have isolated a mouse strain with a single missense mutation, MlklD139V, that alters the two-helix 'brace' that connects the killer four-helix bundle and regulatory pseudokinase domains. This confers constitutive, RIPK3 independent killing activity to MLKL. Homozygous mutant mice develop lethal postnatal inflammation of the salivary glands and mediastinum. The normal embryonic development of MlklD139V homozygotes until birth, and the absence of any overt phenotype in heterozygotes provides important in vivo precedent for the capacity of cells to clear activated MLKL. These observations offer an important insight into the potential disease-modulating roles of three common human MLKL polymorphisms that encode amino acid substitutions within or adjacent to the brace region. Compound heterozygosity of these variants is found at up to 12-fold the expected frequency in patients that suffer from a pediatric autoinflammatory disease, chronic recurrent multifocal osteomyelitis (CRMO).

Presented By Joanne Hildebrand

Cell & Developmental Bio, Biochemistry, MedicineNicholas Liao2020-06 (Jun)