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A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction
- Source :
- Nature Communications, Vol 11, Iss 1, Pp 1-16 (2020), Nature Communications, NATURE COMMUNICATIONS
- Publication Year :
- 2020
- Publisher :
- Nature Publishing Group, 2020.
-
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).<br />Necroptosis is a regulated form of inflammatory cell death driven by activated MLKL. Here, the authors identify a mutation in the brace region that confers constitutive activation, leading to lethal inflammation in homozygous mutant mice and providing insight into human mutations in this region.
- Subjects :
- 0301 basic medicine
Programmed cell death
Necroptosis
Hematopoietic System
Science
Mutation, Missense
General Physics and Astronomy
Biology
Inflammatory diseases
Compound heterozygosity
medicine.disease_cause
General Biochemistry, Genetics and Molecular Biology
Article
03 medical and health sciences
Mice
0302 clinical medicine
medicine
Missense mutation
Animals
Humans
lcsh:Science
Inflammation
Mutation
Multidisciplinary
Haematopoietic stem cells
Chronic recurrent multifocal osteomyelitis
Hereditary Autoinflammatory Diseases
Heterozygote advantage
Osteomyelitis
General Chemistry
medicine.disease
Hematopoietic Stem Cells
Phenotype
030104 developmental biology
Animals, Newborn
Cancer research
lcsh:Q
Protein Kinases
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 11
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....ead403f9f5ff09d2fd122f72a19f707f