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

71 Citations (SciVal)

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 (VoR) - 1 Dec 2020

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10.1038/s41467-020-16819-z

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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{f59ba343ac5e4fc6a54457814759aaba,

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

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 = "Funding Information: MLKL variant quantification. 1000 Genomes: Vcf files from 1000 genomes were annotated and filtered as described previously79. Values for MLKL variants rs35589326 (S132P), rs34515646 (R146Q), and rs144526386 (G202V) as well as all MLKL coding variants were queried and tabulated for allele and genotype count for participants of all ancestry (n = 2504), and for those of European ancestry (n = 503). Compound heterozygous variants were evident due to the phasing of all variants in the 1000 genomes dataset. CRMO: Allele and genotype counts for all MLKL coding variants were tabulated in probands of European ancestry (n = 101) and for all probands (n = 128). Compound heterozygous variants were identified using parental sequence data. AS: DNA from all subjects in AS cohort were gen-otyped using the Illumina CoreExome chip following standard protocols at the Australian Translational Genomics Centre, Princess Alexandra Hospital, Brisbane. Bead intensity data was processed and normalized for each sample and genotypes called using the Illumina Genome Studio software. All the samples listed in the table have passed quality control process80. GB: Genotyping was performed in an ISO15189-accredited clinical genomics facility, Australian Translational Genomics Centre (ATGC), Queensland University of Technology. All samples were geno-typed by Illumina HumanOmniExpress (OmniExpress) BeadChip81. QUT controls: A collection of healthy control data of verified European ancestry from various cohort studies, complied by the Translational Genomics Group, QUT and typed on an Illumina CoreExome microarray. Includes data from The UK Household Longitudinal Study, led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The survey was conducted by NatCen and the genome-wide scan data were analysed and deposited by the Wellcome Trust Sanger Institute. University of Essex. Institute for Social and Economic Research, N. S. R., Kantar Public. Understanding Society: Waves 1–8, 2009–2017 and Harmonised BHPS: Waves 1–18, 1991–2009. [data collection]. 11th Edition. UK Data Service., (2018). Funding Information: We thank all the following people for their technical assistance; Jiami Han, Cynthia Liu, Jasmine McManus, Janelle Lochland and Emma Tovey (WEHI), Aira Nuguid and Tina Cardamone (APN histopathology – The University of Melbourne). Thomas Boudier (WEHI Centre for Dynamic Imaging). The WEHI Histology Service, WEHI Antibody Facility and WEHI Bioservices. Y. Uchiyama and S. Kakuta who advised the interpretation of the results of TEM and Annette Jacobsen (WEHI) for important insight and discussion. The generation of MlklD139V mice by CRISPR/Cas9 was performed by Andrew Kueh and Marco Herold (WEHI MAGEC laboratory) supported by the Australian Phenomics Network (APN) and the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. This work is supported by; Project grant (1105023) and Fellowships (0541951 and 1142669) from the Australian National Health and Medical Research Council (NHMRC) to J.M. H.; Fellowship (1107149) from the NHMRC to J.S.; Program grant (1113577) and Fellowship (1058344) from the NHMRC (W.S.A.); Project grant (1124735) and Fellowships (1105754, 1172929) from the NHMRC (J.M.M.); NIH training grants T32GM008629 and T32GM082729-01 (A.J.C.); R01AR059703 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at the National Institutes of Health (P.J.F. and A.G.B.); the Marjorie K. Lamb Professorship (P.J.F.); Grants-in-Aid from Scientific Research (B) 17H04069 from Japan Society for the Promotion of Science, and Scientific Research on Innovative areas 26110003, the Japan Agency for Medical Research and Development (AMED) through AMED-CREST JP20gm1210002 and Private University Research Branding project from a MEXT (H. N.); Victorian International Research Scholarship (Z.L. and M.C.T.). Australia Post-graduate Award (C.A.D.); S.L.M. acknowledges funding from NHMRC grants (1144282, 1142354, and 1099262), The Sylvia and Charles Viertel Foundation, HHMI-Wellcome International Research Scholarship and Glaxosmithkline; Fellowship from the Lorenzo and Pamela Galli Charitable Trust (E.C.J.), NHMRC grants 1107425 and 1045549 and The Sylvia & Charles Viertel Senior Medical Research Fellowship (M.P.); D.B.A. was supported by the Jack Brockhoff Foundation (JBF 4186, 2016) and NHMRC Fellowship (APP1072476); NHMRC IRIISS 9000587 and Victorian Government Operational Infrastructure Support schemes; NHMRC Project and Targeted Research grants 1006769, 512672, and 512381 (M.F.S.); The Department of Industry, Innovation, Science, Research and Tertiary Education Collaborative Research Network and Diabetes Australia (MAB); I.J.M. was supported by the Victorian Cancer Agency, and by generous support from the Felton Bequest; Cancer Australia and Leukemia Foundation Australia priority grant (PdCCRS 1162023) and a Victoria Cancer Agency (VCA) mid-career fellowship (MCRF 15027) to G.B. We gratefully acknowledge the contribution of genotype data by Dr Yorgi Mavros (University of Sydney), Professor Nick Martin (QIMR), Professor Jim Rosenbaum (Oregon Health and Science University), and Professor Maxime Breban and the Groupe Fran{\c c}aise d{\textquoteright}Etude G{\'e}n{\'e}tique des Spondylarthrites (GFEGS). We are grateful to Professor BP Wordsworth of the University of Oxford, UK for access to genotype data on ankylosing spondylitis cases collected in studies funded, in part, by Arthritis Research UK (grants 19536 and 18797), by the Wellcome Trust (grant 076113) and by the Oxford Comprehensive Biomedical Research Centre ankylosing spondylitis chronic disease cohort (theme A91202). 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",

publisher = "Nature Research",

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

N1 - Funding Information: MLKL variant quantification. 1000 Genomes: Vcf files from 1000 genomes were annotated and filtered as described previously79. Values for MLKL variants rs35589326 (S132P), rs34515646 (R146Q), and rs144526386 (G202V) as well as all MLKL coding variants were queried and tabulated for allele and genotype count for participants of all ancestry (n = 2504), and for those of European ancestry (n = 503). Compound heterozygous variants were evident due to the phasing of all variants in the 1000 genomes dataset. CRMO: Allele and genotype counts for all MLKL coding variants were tabulated in probands of European ancestry (n = 101) and for all probands (n = 128). Compound heterozygous variants were identified using parental sequence data. AS: DNA from all subjects in AS cohort were gen-otyped using the Illumina CoreExome chip following standard protocols at the Australian Translational Genomics Centre, Princess Alexandra Hospital, Brisbane. Bead intensity data was processed and normalized for each sample and genotypes called using the Illumina Genome Studio software. All the samples listed in the table have passed quality control process80. GB: Genotyping was performed in an ISO15189-accredited clinical genomics facility, Australian Translational Genomics Centre (ATGC), Queensland University of Technology. All samples were geno-typed by Illumina HumanOmniExpress (OmniExpress) BeadChip81. QUT controls: A collection of healthy control data of verified European ancestry from various cohort studies, complied by the Translational Genomics Group, QUT and typed on an Illumina CoreExome microarray. Includes data from The UK Household Longitudinal Study, led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The survey was conducted by NatCen and the genome-wide scan data were analysed and deposited by the Wellcome Trust Sanger Institute. University of Essex. Institute for Social and Economic Research, N. S. R., Kantar Public. Understanding Society: Waves 1–8, 2009–2017 and Harmonised BHPS: Waves 1–18, 1991–2009. [data collection]. 11th Edition. UK Data Service., (2018). Funding Information: We thank all the following people for their technical assistance; Jiami Han, Cynthia Liu, Jasmine McManus, Janelle Lochland and Emma Tovey (WEHI), Aira Nuguid and Tina Cardamone (APN histopathology – The University of Melbourne). Thomas Boudier (WEHI Centre for Dynamic Imaging). The WEHI Histology Service, WEHI Antibody Facility and WEHI Bioservices. Y. Uchiyama and S. Kakuta who advised the interpretation of the results of TEM and Annette Jacobsen (WEHI) for important insight and discussion. The generation of MlklD139V mice by CRISPR/Cas9 was performed by Andrew Kueh and Marco Herold (WEHI MAGEC laboratory) supported by the Australian Phenomics Network (APN) and the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. This work is supported by; Project grant (1105023) and Fellowships (0541951 and 1142669) from the Australian National Health and Medical Research Council (NHMRC) to J.M. H.; Fellowship (1107149) from the NHMRC to J.S.; Program grant (1113577) and Fellowship (1058344) from the NHMRC (W.S.A.); Project grant (1124735) and Fellowships (1105754, 1172929) from the NHMRC (J.M.M.); NIH training grants T32GM008629 and T32GM082729-01 (A.J.C.); R01AR059703 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at the National Institutes of Health (P.J.F. and A.G.B.); the Marjorie K. Lamb Professorship (P.J.F.); Grants-in-Aid from Scientific Research (B) 17H04069 from Japan Society for the Promotion of Science, and Scientific Research on Innovative areas 26110003, the Japan Agency for Medical Research and Development (AMED) through AMED-CREST JP20gm1210002 and Private University Research Branding project from a MEXT (H. N.); Victorian International Research Scholarship (Z.L. and M.C.T.). Australia Post-graduate Award (C.A.D.); S.L.M. acknowledges funding from NHMRC grants (1144282, 1142354, and 1099262), The Sylvia and Charles Viertel Foundation, HHMI-Wellcome International Research Scholarship and Glaxosmithkline; Fellowship from the Lorenzo and Pamela Galli Charitable Trust (E.C.J.), NHMRC grants 1107425 and 1045549 and The Sylvia & Charles Viertel Senior Medical Research Fellowship (M.P.); D.B.A. was supported by the Jack Brockhoff Foundation (JBF 4186, 2016) and NHMRC Fellowship (APP1072476); NHMRC IRIISS 9000587 and Victorian Government Operational Infrastructure Support schemes; NHMRC Project and Targeted Research grants 1006769, 512672, and 512381 (M.F.S.); The Department of Industry, Innovation, Science, Research and Tertiary Education Collaborative Research Network and Diabetes Australia (MAB); I.J.M. was supported by the Victorian Cancer Agency, and by generous support from the Felton Bequest; Cancer Australia and Leukemia Foundation Australia priority grant (PdCCRS 1162023) and a Victoria Cancer Agency (VCA) mid-career fellowship (MCRF 15027) to G.B. We gratefully acknowledge the contribution of genotype data by Dr Yorgi Mavros (University of Sydney), Professor Nick Martin (QIMR), Professor Jim Rosenbaum (Oregon Health and Science University), and Professor Maxime Breban and the Groupe Française d’Etude Génétique des Spondylarthrites (GFEGS). We are grateful to Professor BP Wordsworth of the University of Oxford, UK for access to genotype data on ankylosing spondylitis cases collected in studies funded, in part, by Arthritis Research UK (grants 19536 and 18797), by the Wellcome Trust (grant 076113) and by the Oxford Comprehensive Biomedical Research Centre ankylosing spondylitis chronic disease cohort (theme A91202). Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

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U2 - 10.1038/s41467-020-16819-z

DO - 10.1038/s41467-020-16819-z

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JO - Nature Communications

JF - Nature Communications

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ER -

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

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