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 Di 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 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; 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; John Silke

doi:10.1038/s41467-020-16819-z

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

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Open access

Peer reviewed

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, …

Nature communications, Vol.11(1), pp.3150-3150

06/19/2020

DOI: 10.1038/s41467-020-16819-z

PMCID: PMC7305203

PMID: 32561755

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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, Mlkl , 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 Mlkl 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).

Animals, Newborn

Protein Kinases - metabolism

Protein Kinases - genetics

Hereditary Autoinflammatory Diseases

Humans

Osteomyelitis - genetics

Hematopoietic Stem Cells - metabolism

Mutation, Missense

Necroptosis - genetics

Animals

Inflammation - genetics

Mice

Hematopoietic System - pathology

Details

Title: Subtitle: A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction
Creators: Joanne M Hildebrand - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia. jhildebrand@wehi.edu.au
Maria Kauppi - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Ian J Majewski - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Zikou Liu - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Allison J Cox - University of Iowa, Stead Family Department of Pediatrics
Sanae Miyake - Department of Biochemistry, Toho University School of Medicine, Ota-ku, Tokyo, 143-8540, Japan
Emma J Petrie - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Michael A Silk - Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
Zhixiu Li - Translational Genomics Group, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT) at Translational Research Institute, Brisbane, Australia
Maria C Tanzer - Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, 82152, Germany
Gabriela Brumatti - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Samuel N Young - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Cathrine Hall - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Sarah E Garnish - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Jason Corbin - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Michael D Stutz - Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, 97006, USA
Ladina Di Rago - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Pradnya Gangatirkar - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Emma C Josefsson - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Kristin Rigbye - Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, 3052, Australia
Holly Anderton - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
James A Rickard - The Royal Melbourne Hospital, Melbourne, VIC, 3050, Australia
Anne Tripaydonis - The Royal Melbourne Hospital, Melbourne, VIC, 3050, Australia
Julie Sheridan - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Thomas S Scerri - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Victoria E Jackson - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Peter E Czabotar - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Jian-Guo Zhang - University of Iowa, Pathology
Leila Varghese - Ludwig Institute for Cancer Research and de Duve Institute, Brussels, Belgium
Cody C Allison - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Marc Pellegrini - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Gillian M Tannahill - GSK Medicines Research Centre, Stevenage, UK
Esme C Hatchell - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Tracy A Willson - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Dina Stockwell - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Carolyn A de Graaf - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Janelle Collinge - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Adrienne Hilton - The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia
Natasha Silke - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Sukhdeep K Spall - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Diep Chau - CSL Limited, Parkville, VIC, 3052, Australia
Vicki Athanasopoulos - Centre for Personalised Immunology (CACPI), Shanghai Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
Donald Metcalf - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Ronald M Laxer - Division of Rheumatology, The Hospital for Sick Children and the University of Toronto, Toronto, ON, Canada
Alexander G Bassuk - University of Iowa, Stead Family Department of Pediatrics
Benjamin W Darbro - University of Iowa, Stead Family Department of Pediatrics
Maria A Fiatarone Singh - Faculty of Health Sciences and Sydney Medical School, University of Sydney, Sydney, Australia
Nicole Vlahovich - Department of Sports Medicine, Australian Institute of Sport, Bruce, ACT, Australia
David Hughes - University of Iowa, Internal Medicine
Maria Kozlovskaia - Faculty of Health, University of Canberra, Canberra, Australia
David B Ascher - Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
Klaus Warnatz - Center for Chronic Immunodeficiency, Medical Center -University of Freiburg, Faculty of Medicine, Freiburg, Germany
Nils Venhoff - Department of Internal Medicine, Clinic for Rheumatology and Clinical Immunology, Medical Center -University of Freiburg, Faculty of Medicine, Freiburg, 79106, Germany
Jens Thiel - Department of Internal Medicine, Clinic for Rheumatology and Clinical Immunology, Medical Center -University of Freiburg, Faculty of Medicine, Freiburg, 79106, Germany
Christine Biben - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Stefan Blum - Princess Alexandra Hospital, Brisbane, QLD, Australia
John Reveille - Memorial Hermann Texas Medical Centre, Houston, TX, USA
Michael S Hildebrand - Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC, 3052, Australia
Carola G Vinuesa - Centre for Personalised Immunology (CACPI), Shanghai Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
Pamela McCombe - The University of Queensland, UQ Centre for Clinical Research, Royal Brisbane & Women's Hospital, Brisbane, Australia
Matthew A Brown - Princess Alexandra Hospital
Benjamin T Kile - Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia
Catriona McLean - Department of Anatomical Pathology, The Alfred Hospital, Prahran, VIC, 3181, Australia
Melanie Bahlo - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Seth L Masters - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Hiroyasu Nakano - Department of Biochemistry, Toho University School of Medicine, Ota-ku, Tokyo, 143-8540, Japan
Polly J Ferguson - University of Iowa, Stead Family Department of Pediatrics
James M Murphy - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia
Warren S Alexander - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia. alexandw@wehi.edu.au
John Silke - Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia. silke@wehi.edu.au
Resource Type: Journal article
Publication Details: Nature communications, Vol.11(1), pp.3150-3150
DOI: 10.1038/s41467-020-16819-z
PMID: 32561755
PMCID: PMC7305203
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: 18797 / Arthritis Research UK T32 GM008629 / NIGMS NIH HHS T32 GM082729 / NIGMS NIH HHS Wellcome Trust R01 AR059703 / NIAMS NIH HHS 19536 / Arthritis Research UK 076113 / Wellcome Trust
Language: English
Date published: 06/19/2020
Academic Unit: Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Rheumatology, Allergy, and Immunology; Neurology (Pediatrics); Internal Medicine
Record Identifier: 9984070827702771

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