Munoz, Marcia A. and Skinner, Oliver P. and Masle-Farquhar, Etienne and Jurczyluk, Julie and Xiao, Ya and Fletcher, Emma K. and Kristianto, Esther and Hodson, Mark P. and O’Donoghue, Seán I. and Kaur, Sandeep and Brink, Robert and Zahra, David G. and Deenick, Elissa K. and Perry, Kristen A. and Robertson, Avril A.B. and Mehr, Sam and Hissaria, Pravin and Mulders-Manders, Catharina M. and Simon, Anna and Rogers, Michael J. (2022) Increased core body temperature exacerbates defective protein prenylation in mouse models of mevalonate kinase deficiency. Journal of Clinical Investigation, 132 (19). ISSN 1558-8238
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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. © 2022, Munoz et al.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 03 Mar 2023 00:56 |
| Last Modified: | 20 Mar 2023 02:36 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/1315 |
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