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

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 RigbyeHolly 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

73 Citations (Scopus)

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).

Original language	English
Article number	3150
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16819-z
Publication status	Published - 1 Dec 2020

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Hildebrand, J. M., Kauppi, M., Majewski, I. J., Liu, Z., Cox, A. J., Miyake, S., Petrie, E. J., Silk, M. A., Li, Z., Tanzer, M. C., Brumatti, G., Young, S. N., Hall, C., Garnish, S. E., Corbin, J., Stutz, M. D., Di Rago, L., Gangatirkar, P., Josefsson, E. C., ... Silke, J. (2020). A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction. Nature Communications, 11(1), Article 3150. https://doi.org/10.1038/s41467-020-16819-z

@article{ace5b9ef61874af48f6badc7f112ff2d,

title = "A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction",

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 {\textquoteleft}brace{\textquoteright} 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).",

author = "Hildebrand, {Joanne M.} and Maria Kauppi and Majewski, {Ian J.} and Zikou Liu and Cox, {Allison J.} and Sanae Miyake and Petrie, {Emma J.} and Silk, {Michael A.} and Zhixiu Li and Tanzer, {Maria C.} and Gabriela Brumatti and Young, {Samuel N.} and Cathrine Hall and Garnish, {Sarah E.} and Jason Corbin and Stutz, {Michael D.} and {Di Rago}, Ladina and Pradnya Gangatirkar and Josefsson, {Emma C.} and Kristin Rigbye and Holly Anderton and Rickard, {James A.} and Anne Tripaydonis and Julie Sheridan and Scerri, {Thomas S.} and Jackson, {Victoria E.} and Czabotar, {Peter E.} and Zhang, {Jian Guo} and Leila Varghese and Allison, {Cody C.} and Marc Pellegrini and Tannahill, {Gillian M.} and Hatchell, {Esme C.} and Willson, {Tracy A.} and Dina Stockwell and {de Graaf}, {Carolyn A.} and Janelle Collinge and Adrienne Hilton and Natasha Silke and Spall, {Sukhdeep K.} and Diep Chau and Vicki Athanasopoulos and Donald Metcalf and Laxer, {Ronald M.} and Bassuk, {Alexander G.} and Darbro, {Benjamin W.} and {Fiatarone Singh}, {Maria A.} and Nicole Vlahovich and David Hughes and Maria Kozlovskaia and Ascher, {David B.} and Klaus Warnatz and Nils Venhoff and Jens Thiel and Christine Biben and Stefan Blum and John Reveille and Hildebrand, {Michael S.} and Vinuesa, {Carola G.} and Pamela McCombe and Brown, {Matthew A.} and Kile, {Benjamin T.} and Catriona McLean and Melanie Bahlo and Masters, {Seth L.} and Hiroyasu Nakano and Ferguson, {Polly J.} and Murphy, {James M.} and Alexander, {Warren S.} and John Silke",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-16819-z",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Hildebrand, JM, Kauppi, M, Majewski, IJ, Liu, Z, Cox, AJ, Miyake, S, Petrie, EJ, Silk, MA, Li, Z, Tanzer, MC, Brumatti, G, Young, SN, Hall, C, Garnish, SE, Corbin, J, Stutz, MD, Di Rago, L, Gangatirkar, P, Josefsson, EC, Rigbye, K, Anderton, H, Rickard, JA, Tripaydonis, A, Sheridan, J, Scerri, TS, Jackson, VE, Czabotar, PE, Zhang, JG, Varghese, L, Allison, CC, Pellegrini, M, Tannahill, GM, Hatchell, EC, Willson, TA, Stockwell, D, de Graaf, CA, Collinge, J, Hilton, A, Silke, N, Spall, SK, Chau, D, Athanasopoulos, V, Metcalf, D, Laxer, RM, Bassuk, AG, Darbro, BW, Fiatarone Singh, MA, Vlahovich, N, Hughes, D, Kozlovskaia, M, Ascher, DB, Warnatz, K, Venhoff, N, Thiel, J, Biben, C, Blum, S, Reveille, J, Hildebrand, MS, Vinuesa, CG, McCombe, P, Brown, MA, Kile, BT, McLean, C, Bahlo, M, Masters, SL, Nakano, H, Ferguson, PJ, Murphy, JM, Alexander, WS & Silke, J 2020, 'A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction', Nature Communications, vol. 11, no. 1, 3150. https://doi.org/10.1038/s41467-020-16819-z

TY - JOUR

T1 - A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction

AU - Hildebrand, Joanne M.

AU - Kauppi, Maria

AU - Majewski, Ian J.

AU - Liu, Zikou

AU - Cox, Allison J.

AU - Miyake, Sanae

AU - Petrie, Emma J.

AU - Silk, Michael A.

AU - Li, Zhixiu

AU - Tanzer, Maria C.

AU - Brumatti, Gabriela

AU - Young, Samuel N.

AU - Hall, Cathrine

AU - Garnish, Sarah E.

AU - Corbin, Jason

AU - Stutz, Michael D.

AU - Di Rago, Ladina

AU - Gangatirkar, Pradnya

AU - Josefsson, Emma C.

AU - Rigbye, Kristin

AU - Anderton, Holly

AU - Rickard, James A.

AU - Tripaydonis, Anne

AU - Sheridan, Julie

AU - Scerri, Thomas S.

AU - Jackson, Victoria E.

AU - Czabotar, Peter E.

AU - Zhang, Jian Guo

AU - Varghese, Leila

AU - Allison, Cody C.

AU - Pellegrini, Marc

AU - Tannahill, Gillian M.

AU - Hatchell, Esme C.

AU - Willson, Tracy A.

AU - Stockwell, Dina

AU - de Graaf, Carolyn A.

AU - Collinge, Janelle

AU - Hilton, Adrienne

AU - Silke, Natasha

AU - Spall, Sukhdeep K.

AU - Chau, Diep

AU - Athanasopoulos, Vicki

AU - Metcalf, Donald

AU - Laxer, Ronald M.

AU - Bassuk, Alexander G.

AU - Darbro, Benjamin W.

AU - Fiatarone Singh, Maria A.

AU - Vlahovich, Nicole

AU - Hughes, David

AU - Kozlovskaia, Maria

AU - Ascher, David B.

AU - Warnatz, Klaus

AU - Venhoff, Nils

AU - Thiel, Jens

AU - Biben, Christine

AU - Blum, Stefan

AU - Reveille, John

AU - Hildebrand, Michael S.

AU - Vinuesa, Carola G.

AU - McCombe, Pamela

AU - Brown, Matthew A.

AU - Kile, Benjamin T.

AU - McLean, Catriona

AU - Bahlo, Melanie

AU - Masters, Seth L.

AU - Nakano, Hiroyasu

AU - Ferguson, Polly J.

AU - Murphy, James M.

AU - Alexander, Warren S.

AU - Silke, John

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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).

AB - 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).

UR - http://www.scopus.com/inward/record.url?scp=85086677563&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-16819-z

DO - 10.1038/s41467-020-16819-z

M3 - Article

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3150

ER -

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

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