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

2020-06-19

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

Journal Article

0000-0002-1456-2042

0000-0003-3913-9686

0000-0002-0787-5083

0000-0003-2739-0515

0000-0002-9298-1728

0000-0001-6478-5204

0000-0002-1478-3662

0000-0003-0992-4042

0000-0002-2594-496X

0000-0003-2476-0306

0000-0001-8380-5311

0000-0002-4067-2157

0000-0003-2948-2413

0000-0003-4387-8676

0000-0003-2704-8517

0000-0003-0538-8211

0000-0002-8836-8947

0000-0002-0302-5727

0000-0001-5132-0774

0000-0003-4763-576X

0000-0003-4843-1427

0000-0003-0195-3949

0000-0002-7611-5774

10.1038/s41467-020-16819-z

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).

link

Nature Communications 2020; 11(1): 3150

Nature Communications