Please use this identifier to cite or link to this item:
Title: A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction.
Austin Authors: Hildebrand, Joanne M;Kauppi, Maria;Majewski, Ian J;Liu, Zikou;Cox, Allison J;Miyake, Sanae;Petrie, Emma J;Silk, Michael A;Li, Zhixiu;Tanzer, Maria C;Brumatti, Gabriela;Young, Samuel N;Hall, Cathrine;Garnish, Sarah E;Corbin, Jason;Stutz, Michael D;Di Rago, Ladina;Gangatirkar, Pradnya;Josefsson, Emma C;Rigbye, Kristin;Anderton, Holly;Rickard, James A;Tripaydonis, Anne;Sheridan, Julie;Scerri, Thomas S;Jackson, Victoria E;Czabotar, Peter E;Zhang, Jian-Guo;Varghese, Leila;Allison, Cody C;Pellegrini, Marc;Tannahill, Gillian M;Hatchell, Esme C;Willson, Tracy A;Stockwell, Dina;de Graaf, Carolyn A;Collinge, Janelle;Hilton, Adrienne;Silke, Natasha;Spall, Sukhdeep K;Chau, Diep;Athanasopoulos, Vicki;Metcalf, Donald;Laxer, Ronald M;Bassuk, Alexander G;Darbro, Benjamin W;Fiatarone Singh, Maria A;Vlahovich, Nicole;Hughes, David;Kozlovskaia, Maria;Ascher, David B;Warnatz, Klaus;Venhoff, Nils;Thiel, Jens;Biben, Christine;Blum, Stefan;Reveille, John;Hildebrand, Michael S ;Vinuesa, Carola G;McCombe, Pamela;Brown, Matthew A;Kile, Benjamin T;McLean, Catriona;Bahlo, Melanie;Masters, Seth L;Nakano, Hiroyasu;Ferguson, Polly J;Murphy, James M;Alexander, Warren S;Silke, John
Affiliation: Faculty of Health Sciences and Sydney Medical School, University of Sydney, Sydney, Australia
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, 97006, USA
Division of Rheumatology, The Hospital for Sick Children and the University of Toronto, Toronto, ON, Canada
NIHR Biomedical Research Centre, Kings College, London, UK
GSK Medicines Research Centre, Stevenage, UK
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia
Department of Anatomical Pathology, The Alfred Hospital, Prahran, VIC, 3181, Australia
Translational Genomics Group, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT) at Translational Research Institute, Brisbane, Australia
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
Centre for Personalised Immunology (CACPI), Shanghai Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
Department of Internal Medicine, Clinic for Rheumatology and Clinical Immunology, Medical Center -University of Freiburg, Faculty of Medicine, Freiburg, 79106, Germany
Center for Chronic Immunodeficiency, Medical Center -University of Freiburg, Faculty of Medicine, Freiburg, Germany
Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Ludwig Institute for Cancer Research and de Duve Institute, Brussels, Belgium
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, 82152, Germany
Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Melbourne, VIC, 3052, Australia
Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, 3052, Australia
The Royal Melbourne Hospital, Melbourne, VIC, 3050, Australia
CSL Limited, Parkville, VIC, 3052, Australia
Department of Sports Medicine, Australian Institute of Sport, Bruce, ACT, Australia
Faculty of Health, University of Canberra, Canberra, Australia
Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia
The University of Queensland, UQ Centre for Clinical Research, Royal Brisbane & Women's Hospital, Brisbane, Australia
Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC, 3052, Australia
Princess Alexandra Hospital, Brisbane, QLD, Australia
Memorial Hermann Texas Medical Centre, Houston, TX, USA
Department of Neurology, University of Iowa Carver College of Medicine and the Iowa Neuroscience Institute, Iowa City, IA, USA
Department of Biochemistry, Toho University School of Medicine, Ota-ku, Tokyo, 143-8540, Japan
Department of Internal Medicine, Clinic for Rheumatology and Clinical Immunology, Medical Center -University of Freiburg, Faculty of Medicine, Freiburg, 79106, Germany
Department of Biochemistry, Toho University School of Medicine, Ota-ku, Tokyo, 143-8540, Japan
Issue Date: 19-Jun-2020
Date: 2020-06-19
Publication information: Nature Communications 2020; 11(1): 3150
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).
DOI: 10.1038/s41467-020-16819-z
ORCID: 0000-0002-1456-2042
Journal: Nature Communications
PubMed URL: 32561755
Type: Journal Article
Appears in Collections:Journal articles

Show full item record

Page view(s)

checked on Apr 15, 2024

Google ScholarTM


Items in AHRO are protected by copyright, with all rights reserved, unless otherwise indicated.