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

Joanne M. Hildebrand (), Maria Kauppi, Ian J. Majewski, Zikou Liu, Allison J. Cox, Sanae Miyake, Emma J. Petrie, Michael A. Silk, Zhixiu Li, Maria C. Tanzer, Gabriela Brumatti, Samuel N. Young, Cathrine Hall, Sarah E. Garnish, Jason Corbin, Michael D. Stutz, Ladina Rago, Pradnya Gangatirkar, Emma C. Josefsson, Kristin Rigbye, Holly Anderton, James A. Rickard, Anne Tripaydonis, Julie Sheridan, Thomas S. Scerri, Victoria E. Jackson, Peter E. Czabotar, Jian-Guo Zhang, Leila Varghese, Cody C. Allison, Marc Pellegrini, Gillian M. Tannahill, Esme C. Hatchell, Tracy A. Willson, Dina Stockwell, Carolyn A. Graaf, Janelle Collinge, Adrienne Hilton, Natasha Silke, Sukhdeep K. Spall, Diep Chau, Vicki Athanasopoulos, Donald Metcalf, Ronald M. Laxer, Alexander G. Bassuk, Benjamin W. Darbro, Maria A. Fiatarone Singh, Nicole Vlahovich, David Hughes, Maria Kozlovskaia, David B. Ascher, Klaus Warnatz, Nils Venhoff, Jens Thiel, Christine Biben, Stefan Blum, John Reveille, Michael S. Hildebrand, Carola G. Vinuesa, Pamela McCombe, Matthew A. Brown, Benjamin T. Kile, Catriona McLean, Melanie Bahlo, Seth L. Masters, Hiroyasu Nakano, Polly J. Ferguson, James M. Murphy, Warren S. Alexander () and John Silke ()
Additional contact information
Joanne M. Hildebrand: The Walter and Eliza Hall Institute of Medical Research
Maria Kauppi: The Walter and Eliza Hall Institute of Medical Research
Ian J. Majewski: The Walter and Eliza Hall Institute of Medical Research
Zikou Liu: The Walter and Eliza Hall Institute of Medical Research
Allison J. Cox: University of Iowa Carver College of Medicine
Sanae Miyake: Toho University School of Medicine, Ota-ku
Emma J. Petrie: The Walter and Eliza Hall Institute of Medical Research
Michael A. Silk: University of Melbourne
Zhixiu Li: Queensland University of Technology (QUT) at Translational Research Institute
Maria C. Tanzer: The Walter and Eliza Hall Institute of Medical Research
Gabriela Brumatti: The Walter and Eliza Hall Institute of Medical Research
Samuel N. Young: The Walter and Eliza Hall Institute of Medical Research
Cathrine Hall: The Walter and Eliza Hall Institute of Medical Research
Sarah E. Garnish: The Walter and Eliza Hall Institute of Medical Research
Jason Corbin: The Walter and Eliza Hall Institute of Medical Research
Michael D. Stutz: The Walter and Eliza Hall Institute of Medical Research
Ladina Rago: The Walter and Eliza Hall Institute of Medical Research
Pradnya Gangatirkar: The Walter and Eliza Hall Institute of Medical Research
Emma C. Josefsson: The Walter and Eliza Hall Institute of Medical Research
Kristin Rigbye: The Walter and Eliza Hall Institute of Medical Research
Holly Anderton: The Walter and Eliza Hall Institute of Medical Research
James A. Rickard: The Walter and Eliza Hall Institute of Medical Research
Anne Tripaydonis: The Walter and Eliza Hall Institute of Medical Research
Julie Sheridan: The Walter and Eliza Hall Institute of Medical Research
Thomas S. Scerri: The Walter and Eliza Hall Institute of Medical Research
Victoria E. Jackson: The Walter and Eliza Hall Institute of Medical Research
Peter E. Czabotar: The Walter and Eliza Hall Institute of Medical Research
Jian-Guo Zhang: The Walter and Eliza Hall Institute of Medical Research
Leila Varghese: The Walter and Eliza Hall Institute of Medical Research
Cody C. Allison: The Walter and Eliza Hall Institute of Medical Research
Marc Pellegrini: The Walter and Eliza Hall Institute of Medical Research
Gillian M. Tannahill: The Walter and Eliza Hall Institute of Medical Research
Esme C. Hatchell: The Walter and Eliza Hall Institute of Medical Research
Tracy A. Willson: The Walter and Eliza Hall Institute of Medical Research
Dina Stockwell: The Walter and Eliza Hall Institute of Medical Research
Carolyn A. Graaf: The Walter and Eliza Hall Institute of Medical Research
Janelle Collinge: The Walter and Eliza Hall Institute of Medical Research
Adrienne Hilton: The Walter and Eliza Hall Institute of Medical Research
Natasha Silke: The Walter and Eliza Hall Institute of Medical Research
Sukhdeep K. Spall: The Walter and Eliza Hall Institute of Medical Research
Diep Chau: The Walter and Eliza Hall Institute of Medical Research
Vicki Athanasopoulos: Australian National University
Donald Metcalf: The Walter and Eliza Hall Institute of Medical Research
Ronald M. Laxer: The Hospital for Sick Children and the University of Toronto
Alexander G. Bassuk: University of Iowa Carver College of Medicine
Benjamin W. Darbro: University of Iowa Carver College of Medicine
Maria A. Fiatarone Singh: University of Sydney
Nicole Vlahovich: Australian Institute of Sport
David Hughes: Australian Institute of Sport
Maria Kozlovskaia: Australian Institute of Sport
David B. Ascher: University of Melbourne
Klaus Warnatz: Medical Center –University of Freiburg, Faculty of Medicine
Nils Venhoff: Medical Center –University of Freiburg, Faculty of Medicine
Jens Thiel: Medical Center –University of Freiburg, Faculty of Medicine
Christine Biben: The Walter and Eliza Hall Institute of Medical Research
Stefan Blum: Princess Alexandra Hospital
John Reveille: Memorial Hermann Texas Medical Centre
Michael S. Hildebrand: University of Melbourne, Austin Health
Carola G. Vinuesa: Australian National University
Pamela McCombe: Royal Brisbane & Women’s Hospital
Matthew A. Brown: Queensland University of Technology (QUT) at Translational Research Institute
Benjamin T. Kile: The Walter and Eliza Hall Institute of Medical Research
Catriona McLean: The Alfred Hospital
Melanie Bahlo: The Walter and Eliza Hall Institute of Medical Research
Seth L. Masters: The Walter and Eliza Hall Institute of Medical Research
Hiroyasu Nakano: Toho University School of Medicine, Ota-ku
Polly J. Ferguson: University of Iowa Carver College of Medicine
James M. Murphy: The Walter and Eliza Hall Institute of Medical Research
Warren S. Alexander: The Walter and Eliza Hall Institute of Medical Research
John Silke: The Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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).

Date: 2020
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DOI: 10.1038/s41467-020-16819-z

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