Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/136774
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Type: | Journal article |
Title: | Increased core body temperature exacerbates defective protein prenylation in mouse models of mevalonate kinase deficiency |
Author: | Munoz, M.A. Skinner, O.P. Masle-Farquhar, E. Jurczyluk, J. Xiao, Y. Fletcher, E.K. Kristianto, E. Hodson, M.P. O’Donoghue, S.I. Kaur, S. Brink, R. Zahra, D.G. Deenick, E.K. Perry, K.A. Robertson, A.A.B. Mehr, S. Hissaria, P. Mulders-Manders, C.M. Simon, A. Rogers, M.J. |
Citation: | Journal of Clinical Investigation, 2022; 132(19):1-17 |
Publisher: | American Society for Clinical Investigation |
Issue Date: | 2022 |
ISSN: | 0021-9738 1558-8238 |
Statement of Responsibility: | Marcia A. Munoz, Oliver P. Skinner, Etienne Masle-Farquhar, Julie Jurczyluk, Ya Xiao, Emma K. Fletcher, Esther Kristianto, Mark P. Hodson, Seán I. O, Donoghue, Sandeep Kaur, Robert Brink, David G. Zahra, Elissa K. Deenick, Kristen A. Perry, Avril A.B. Robertson, Sam Mehr, Pravin Hissaria, Catharina M. Mulders-Manders, Anna Simon, and Michael J. Rogers |
Abstract: | Mevalonate kinase deficiency (MKD) is characterized by recurrent fevers and flares of systemic inflammation, caused by biallelic loss-of-function mutations in MVK. The underlying disease mechanisms and triggers of inflammatory flares are poorly understood because of the lack of in vivo models. We describe genetically modified mice bearing the hypomorphic mutation p.Val377Ile (the commonest variant in patients with MKD) and amorphic, frameshift mutations in Mvk. Compound heterozygous mice recapitulated the characteristic biochemical phenotype of MKD, with increased plasma mevalonic acid and clear buildup of unprenylated GTPases in PBMCs, splenocytes, and bone marrow. The inflammatory response to LPS was enhanced in compound heterozygous mice and treatment with the NLRP3 inflammasome inhibitor MCC950 prevented the elevation of circulating IL-1β, thus identifying a potential inflammasome target for future therapeutic approaches. Furthermore, lines of mice with a range of deficiencies in mevalonate kinase and abnormal prenylation mirrored the genotype-phenotype relationship in human MKD. Importantly, these mice allowed the determination of a threshold level of residual enzyme activity, below which protein prenylation is impaired. Elevated temperature dramatically but reversibly exacerbated the deficit in the mevalonate pathway and the defective prenylation in vitro and in vivo, highlighting increased body temperature as a likely trigger of inflammatory flares. |
Keywords: | Animals Humans Mice Fever Mevalonic Acid GTP Phosphohydrolases Phosphotransferases (Alcohol Group Acceptor) Lipopolysaccharides Body Temperature Protein Prenylation Mevalonate Kinase Deficiency Inflammasomes NLR Family, Pyrin Domain-Containing 3 Protein |
Rights: | © 2022, Munoz et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. |
DOI: | 10.1172/JCI160929 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1139644 |
Published version: | http://dx.doi.org/10.1172/jci160929 |
Appears in Collections: | Medicine publications |
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hdl_136774.pdf | Published version | 7.69 MB | Adobe PDF | View/Open |
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