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

Hildebrand, J. M., Kauppi, M., Majewski, I. J., Liu, Z., Cox, A. J., Miyake, S., et al. (2020). A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction. NATURE COMMUNICATIONS, 11(1). doi:10.1038/s41467-020-16819-z.

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Hildebrand, Joanne M.1, Author
Kauppi, Maria1, Author
Majewski, Ian J.1, Author
Liu, Zikou1, Author
Cox, Allison J.1, Author
Miyake, Sanae1, Author
Petrie, Emma J.1, Author
Silk, Michael A.1, Author
Li, Zhixiu1, Author
Tanzer, Maria C.2, Author              
Brumatti, Gabriela1, Author
Young, Samuel N.1, Author
Hall, Cathrine1, Author
Garnish, Sarah E.1, Author
Corbin, Jason1, Author
Stutz, Michael D.1, Author
Di Rago, Ladina1, Author
Gangatirkar, Pradnya1, Author
Josefsson, Emma C.1, Author
Rigbye, Kristin1, Author
Anderton, Holly1, AuthorRickard, James A.1, AuthorTripaydonis, Anne1, AuthorSheridan, Julie1, AuthorScerri, Thomas S.1, AuthorJackson, Victoria E.1, AuthorCzabotar, Peter E.1, AuthorZhang, Jian-Guo1, AuthorVarghese, Leila1, AuthorAllison, Cody C.1, AuthorPellegrini, Marc1, AuthorTannahill, Gillian M.1, AuthorHatchell, Esme C.1, AuthorWillson, Tracy A.1, AuthorStockwell, Dina1, Authorde Graaf, Carolyn A.1, AuthorCollinge, Janelle1, AuthorHilton, Adrienne1, AuthorSilke, Natasha1, AuthorSpall, Sukhdeep K.1, AuthorChau, Diep1, AuthorAthanasopoulos, Vicki1, AuthorMetcalf, Donald1, AuthorLaxer, Ronald M.1, AuthorBassuk, Alexander G.1, AuthorDarbro, Benjamin W.1, AuthorSingh, Maria A. Fiatarone1, AuthorVlahovich, Nicole1, AuthorHughes, David1, AuthorKozlovskaia, Maria1, AuthorAscher, David B.1, AuthorWarnatz, Klaus1, AuthorVenhoff, Nils1, AuthorThiel, Jens1, AuthorBiben, Christine1, AuthorBlum, Stefan1, AuthorReveille, John1, AuthorHildebrand, Michael S.1, AuthorVinuesa, Carola G.1, AuthorMcCombe, Pamela1, AuthorBrown, Matthew A.1, AuthorKile, Benjamin T.1, AuthorMcLean, Catriona1, AuthorBahlo, Melanie1, AuthorMasters, Seth L.1, AuthorNakano, Hiroyasu1, AuthorFerguson, Polly J.1, AuthorMurphy, James M.1, AuthorAlexander, Warren S.1, AuthorSilke, John1, Author more..
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: MIXED LINEAGE KINASE; DOMAIN-LIKE PROTEIN; CELL-DEATH; PSEUDOKINASE MLKL; MEDIATES NECROPTOSIS; TARGETED DISRUPTION; AUTOIMMUNE-DISEASES; MICE DEFICIENT; APOPTOSIS; GENOME
 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(D139V), 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(D139V) 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). 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.

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Language(s): eng - English
 Dates: 2020
 Publication Status: Published in print
 Pages: 16
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Degree: -

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Title: NATURE COMMUNICATIONS
Source Genre: Journal
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Publ. Info: MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND : NATURE PUBLISHING GROUP
Pages: - Volume / Issue: 11 (1) Sequence Number: - Start / End Page: - Identifier: ISSN: 2041-1723