HMGCS1 Deficiency Is a Novel Immunometabolic Autoinflammatory Disease with Progressive Myositis

The mevalonate kinase (MVK) pathway is an essential metabolic pathway for sterol and isoprenoid synthesis. Non-sterol isoprenoids have critical biological functions in the post-translational modifications of numerous signaling molecules via prenylation, including inflammasomes. A defect in prenylation impacts protein trafficking and localization and increases proinflammatory cytokine production. Deficiency of the enzymes in the MVK pathway is known to cause systemic autoinflammatory diseases with a broad spectrum of clinical manifestations. Anticholesterol drug statins, which block the second enzyme in this pathway, HMG-CoA reductase, can lead to muscle inflammation. We report biallelic loss-of-function variants in the HMGCS1 gene, which encodes for the first enzyme in the MVK pathway, in four patients from three unrelated families who presented with recurrent fever, arthritis, abdominal pain, and progressive myositis. Three patients were homozygous for a rare variant, c.265C>T (p.Arg89Trp), predicted to be deleterious by multiple algorithms. One patient was homozygous for the novel c.572G>C (p.Arg191Pro) variant classified as VUS. The enzyme activity of both mutant HMGCS1 proteins was decreased, suggesting a deleterious effect on the protein function. Preliminary results showed that these missense variants do not affect protein expression or dimerization, which is critical for protein activity. The PBMCs from patients and CRISPR/cas9–edited HMGSC1-deficient cells showed a defect in prenylation, confirming the involvement of the MVK pathway. HMGCS1-deficient cells displayed an elevated level of IL-1β and IL-18 in response to stimulation with Pam3CSK4 and IFNγ, indicating that HMGCS1 deficiency led to inflammasome activation, which was independent of NLRP3 but was dependent on pyrin. UMAP analysis of peripheral blood single-cell RNA sequencing identified two major cell clusters: NK cells and monocytes. The most differentially upregulated pathways include oxygen/CO2 transport genes, cell death genes, and NF-κB signaling. Intracellular cytokine staining identified a significant increase of IL-1 β, IL-6, and IFNγ in all monocyte subsets of affected patients compared with unaffected relatives. RNA sequencing of frozen muscle tissues detected strong type I and II IFN signatures. Treatment with a JAK inhibitor ameliorated systemic and muscle inflammation in two patients. Further studies are in progress to understand the spectrum of immune dysregulation associated with the HMGCS1 deficiency.