Increased core body temperature exacerbates defective protein prenylation in mouse models of mevalonate kinase deficiency
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 de...
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2022-10-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI160929 |
| _version_ | 1797634569295364096 |
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| author | 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 Michael J. Rogers |
| author_facet | 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 Michael J. Rogers |
| author_sort | Marcia A. Munoz |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:09:29Z |
| format | Article |
| id | doaj.art-21b5b88799f3482d9c5c720c2d6c2ea8 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:09:29Z |
| publishDate | 2022-10-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-21b5b88799f3482d9c5c720c2d6c2ea82023-11-07T16:19:23ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-10-0113219Increased core body temperature exacerbates defective protein prenylation in mouse models of mevalonate kinase deficiencyMarcia A. MunozOliver P. SkinnerEtienne Masle-FarquharJulie JurczylukYa XiaoEmma K. FletcherEsther KristiantoMark P. HodsonSeán I. O’DonoghueSandeep KaurRobert BrinkDavid G. ZahraElissa K. DeenickKristen A. PerryAvril A.B. RobertsonSam MehrPravin HissariaCatharina M. Mulders-MandersAnna SimonMichael J. RogersMevalonate 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.https://doi.org/10.1172/JCI160929InflammationMetabolism |
| spellingShingle | 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 Michael J. Rogers Increased core body temperature exacerbates defective protein prenylation in mouse models of mevalonate kinase deficiency The Journal of Clinical Investigation Inflammation Metabolism |
| title | Increased core body temperature exacerbates defective protein prenylation in mouse models of mevalonate kinase deficiency |
| title_full | Increased core body temperature exacerbates defective protein prenylation in mouse models of mevalonate kinase deficiency |
| title_fullStr | Increased core body temperature exacerbates defective protein prenylation in mouse models of mevalonate kinase deficiency |
| title_full_unstemmed | Increased core body temperature exacerbates defective protein prenylation in mouse models of mevalonate kinase deficiency |
| title_short | Increased core body temperature exacerbates defective protein prenylation in mouse models of mevalonate kinase deficiency |
| title_sort | increased core body temperature exacerbates defective protein prenylation in mouse models of mevalonate kinase deficiency |
| topic | Inflammation Metabolism |
| url | https://doi.org/10.1172/JCI160929 |
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