Abstract
The rare autoinflammatory disease mevalonate kinase deficiency (MKD, which includes HIDS and mevalonic aciduria) is caused by recessive, pathogenic variants in the MVK gene encoding mevalonate kinase. Deficiency of this enzyme decreases the synthesis of isoprenoid lipids and thus prevents the normal post-translational prenylation of small GTPase proteins, which then accumulate in their unprenylated form. We recently optimized a sensitive assay capable of detecting unprenylated Rab GTPase proteins in peripheral blood mononuclear cells (PBMCs) and showed that this assay distinguished MKD from other autoinflammatory diseases. We have now analyzed PBMCs from an additional six patients with genetically-confirmed MKD (with different compound heterozygous MVK genotypes), and compared these with PBMCs from three healthy volunteers and four unaffected control individuals heterozygous for the commonest pathogenic variant, MVKV377I. We detected a clear accumulation of unprenylated Rab proteins, as well as unprenylated Rap1A by western blotting, in all six genetically-confirmed MKD patients compared to heterozygous controls and healthy volunteers. Furthermore, in the three subjects for whom measurements of residual mevalonate kinase activity was available, enzymatic activity inversely correlated with the extent of the defect in protein prenylation. Finally, a heterozygous MVKV377I patient presenting with autoinflammatory symptoms did not have defective prenylation, indicating a different cause of disease. These findings support the notion that the extent of loss of enzyme function caused by biallelic MVK variants determines the severity of defective protein prenylation, and the accumulation of unprenylated proteins in PBMCs may be a sensitive and consistent biomarker that could be used to aid, or help rule out, diagnosis of MKD.
Highlights
Mevalonate kinase deficiency (MKD) is a rare, autosomal recessive, autoinflammatory disorder caused by pathogenic variants in the MVK gene (OMIM 251170) encoding the metabolic enzyme mevalonate kinase (MK) [1, 2]
We recently developed a method to detect subtle changes in the prenylation of Rab GTPase proteins [11, 12] and showed in three patients for the first time that prenylation of Rab proteins, as well as Rap1A, is defective in peripheral blood mononuclear cells (PBMCs) from MKD and could be a biomarker that distinguishes this disease from other autoinflammatory disorders with similar clinical features [13]
Viable PBMCs obtained from 4 MKD patients in the Netherlands (P1–P4) demonstrated a clear accumulation of unprenylated Rab GTPases and unprenylated Rap1A (Figure 1A), compared to PBMCs from a healthy control and two unaffected heterozygous carriers of MVKH20N and MVKV377I variants [the latter described previously, [13]]
Summary
Mevalonate kinase deficiency (MKD) is a rare, autosomal recessive, autoinflammatory disorder caused by pathogenic variants in the MVK gene (OMIM 251170) encoding the metabolic enzyme mevalonate kinase (MK) [1, 2]. We recently developed a method to detect subtle changes in the prenylation of Rab GTPase proteins [11, 12] and showed in three patients for the first time that prenylation of Rab proteins, as well as Rap1A, is defective in peripheral blood mononuclear cells (PBMCs) from MKD and could be a biomarker that distinguishes this disease from other autoinflammatory disorders with similar clinical features [13]. It remains to be confirmed whether this assay consistently identifies MKD in patients with diverse MVK genotypes. We analyzed an additional six patients with genetically-confirmed MKD and different compound heterozygous MVK genotypes, four healthy individuals that were heterozygous for the commonest pathogenic variant MVKV377I, one patient with autoinflammatory disease but heterozygous for MVKV377I, and three healthy controls
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