A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction.
Joanne M HildebrandMaria KauppiIan J MajewskiZikou LiuAllison J CoxSanae MiyakeEmma J PetrieMichael A SilkZhixiu LiMaria C TanzerGabriela BrumattiSamuel N YoungCathrine HallSarah E GarnishJason CorbinMichael D StutzLadina Di RagoPradnya GangatirkarEmma C JosefssonKristin RigbyeHolly AndertonJames A RickardAnne TripaydonisJulie M SheridanThomas S ScerriVictoria E JacksonPeter E CzabotarJian-Guo ZhangLeila VargheseCody C AllisonMarc PellegriniGillian M TannahillEsme C HatchellTracy A WillsonDina StockwellCarolyn A de GraafJanelle CollingeAdrienne HiltonNatasha SilkeSukhdeep K SpallDiep ChauVicki AthanasopoulosDonald MetcalfRonald M LaxerAlexander G BassukBenjamin W DarbroMaria A Fiatarone SinghNicole VlahovichDavid HughesMaria KozlovskaiaDavid Benjamin AscherKlaus WarnatzNils VenhoffJens ThielChristine BibenStefan BlumJohn ReveilleMichael S HildebrandCarola G VinuesaPamela A McCombeMatthew A BrownBenjamin T KileCatriona A McleanMelanie BahloSeth L MastersHiroyasu NakanoPolly J FergusonJames G MurphyWarren S AlexanderJohn SilkePublished in: Nature communications (2020)
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).
Keyphrases
- oxidative stress
- cell death
- end stage renal disease
- cell cycle arrest
- induced apoptosis
- amino acid
- intellectual disability
- chronic kidney disease
- endothelial cells
- ejection fraction
- newly diagnosed
- prognostic factors
- signaling pathway
- regulatory t cells
- peritoneal dialysis
- autism spectrum disorder
- copy number
- wild type
- genome wide
- climate change
- metabolic syndrome
- patient reported
- skeletal muscle
- pluripotent stem cells