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Temperature dependence of mutant mevalonate kinase activity as a pathogenic factor in hyper-IgD and periodic fever
Sander M Houten1, Joost Frenkel, Ger T Rijkers
1Departments of Paediatrics/Emma Children's Hospital and Clinical Chemistry, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
Abstract:
Hyper-IgD and periodic fever syndrome (HIDS) and mevalonic aciduria are autosomal recessive disorders characterized by recurrent episodes of fever and generalized inflammation. Both syndromes are caused by specific mutations in the gene encoding mevalonate kinase (MK), resulting in a depressed enzymatic activity mainly due to reduced protein levels. We studied the effect of temperature on the activity of wild-type and several mutant MKs in fibroblasts. All fibroblast cell lines from HIDS patients and harbouring the common V377I MVK allele displayed substantially higher MK activities at 30 degrees C as compared to 37 degrees C. As shown by temperature inactivation experiments this resulted in a protein nearly as stable as in control cell lines, indicating that primarily the maturation of the protein is affected. Accordingly, when HIDS cell lines were cultured at 39 degrees C, MK activity decreased further. This triggered a compensatory increase in 3-hydroxy-3-methylglutaryl-CoA reductase activity, indicating that MK becomes progressively rate-limiting. A similar phenomenon occurs in vivo. MK activity in peripheral blood mononuclear cells drops 2-8-fold when HIDS patients experience febrile attacks. Our results suggest that minor elevations in temperature can set off a chain of events with MK becoming progressively rate-limiting, leading to a temporary deficiency of isoprenoid end-products, which induces inflammation and fever.
Insights
Temperature sensitivity impairs mevalonate kinase (MK) in Hyper-IgD and periodic fever syndrome (HIDS). Lower temperatures increase MK activity, while fever worsens MK deficiency, leading to inflammation.
Area of Science:
- Biochemistry
- Genetics
- Immunology
Background:
- Hyper-IgD and periodic fever syndrome (HIDS) and mevalonic aciduria are rare autosomal recessive autoinflammatory disorders.
- These conditions stem from mutations in the mevalonate kinase (MK) gene, leading to reduced enzyme activity.
Purpose of the Study:
- To investigate the impact of temperature on mevalonate kinase (MK) activity in HIDS patients.
- To elucidate the role of MK deficiency in the pathogenesis of recurrent fevers and inflammation.
Main Methods:
- Culturing patient-derived fibroblasts at different temperatures (30°C, 37°C, 39°C).
- Measuring mevalonate kinase (MK) enzymatic activity.
- Assessing protein stability through temperature inactivation experiments.
- Monitoring 3-hydroxy-3-methylglutaryl-CoA reductase activity.
Main Results:
- Fibroblasts from HIDS patients showed significantly higher MK activity at 30°C compared to 37°C.
- MK protein maturation, not stability, was primarily affected in HIDS.
- Culturing at 39°C further decreased MK activity, triggering compensatory increases in HMG-CoA reductase.
- In vivo, MK activity dropped during febrile attacks in HIDS patients.
Conclusions:
- Minor temperature increases can destabilize MK, making it rate-limiting and causing isoprenoid deficiency.
- This deficiency is a key factor in triggering inflammation and fever in HIDS.
- Understanding temperature's role offers insights into managing HIDS and related disorders.