Missense mutations in the MLKL ‘brace’ region lead to lethal neonatal inflammation in mice and are present in high frequency in humans
Joanne M. Hildebrand, et al.
Received Date: 18th March 20
Joanne M. Hildebrand, Maria Kauppi, Ian J. Majewski, Zikou Liu, Allison Cox, Sanae Miyake, Emma J. Petrie, Michael A. Silk, Zhixiu Li, Maria C. Tanzer, Samuel N. Young, Cathrine Hall, Sarah E. Garnish, Jason Corbin, Michael D. Stutz, Pradnya Gangatirkar, Emma C. Josefsson, Kristin Rigbye, Holly Anderton, James A. Rickard, Anne Tripaydonis, Julie Sheridan, Thomas S. Scerri, Peter A. Czabotar, Jian-Guo Zhang, Cody C. Allison, Marc Pellegrini, Gillian M. Tannahill, Esme C. Hatchell, Tracy A. Willson, Dina Stockwell, Carolyn A. de 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, Stefan Blum, John Reveille, Michael S. Hildebrand, Carola G. Vinuesa, Pamela McCombe, Matthew A. Brown, Ben T. Kile, Catriona McLean, Melanie Bahlo, Seth L. Masters, Hiroyasu Nakano, Polly J. Ferguson, James M. Murphy, Warren S. Alexander, John Silke
We have isolated a mouse strain with a single missense mutation in the gene encoding MLKL, the essential effector of necroptotic cell death. The resulting D139V substitution lies within the two-helix ‘brace’ that connects the killer four-helix bundle and regulatory pseudokinase domains, and confers constitutive, RIPK3 independent, killing activity to MLKL. Homozygous mutant mice develop lethal inflammation within days of birth, implicating the salivary glands and pericardium as hotspots for necroptosis and inflammatory infiltration. The normal 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, CRMO.
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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.