Mevalonate kinase deficiency (MKD) is an inborn error of metabolism caused by autosomal recessive mutations in MVK, leading to <20% residual mevalonate kinase (MK) activity. Recurrent flares of systemic inflammation are commonly triggered by infection, vaccination, stress or exercise (factors that can induce a rise in core body temperature); the underlying mechanisms are unknown due partly to the lack of animal models.
We used gene editing to create Mvk mutant mice bearing a p.Val377Ile substitution (the commonest pathogenic variant) or a 91bp loss-of-function deletion. Compound heterozygous mice had ~9% residual MK activity and recapitulated the biochemical phenotype of MKD, with intracellular build-up of unprenylated GTPase proteins in spleen, bone marrow and circulating immune cells, and a significant increase in plasma mevalonate. Homozygous V377I mice had about 20% residual MK activity and, similar to humans with this genotype, a much milder phenotype. The inflammatory response to in vivo LPS administration was enhanced in compound heterozygous mice compared to heterozygous controls and elevated IL-1β release was abolished by MCC950 treatment, demonstrating a clear role for the NLRP3 inflammasome.
Since previous studies have suggested that mutations may render the MK enzyme heat-sensitive and cause misfolding/degradation, we increased the core body temperature of mice 2 degrees by housing mice for 18 hours at 38°C. MK activity in spleen was unaffected in controls but became almost undetectable in Mvk mutant mice, with a worsened defect in prenylation in spleen cells and further elevation of plasma mevalonate. Culturing mutant mouse macrophages and human MKD patient PBMCs for 24hr at ≥39°C, rather than 37°C, had a similar effect.
Our studies suggest that stress or mild fever may trigger inflammatory flares in MKD via increased core body temperature, leading to worsening of the metabolic defect, further loss of protein prenylation and enhanced NLRP3-dependent inflammasome activation.