HMGCS1 Deficiency Is a Novel Immunometabolic Autoinflammatory Disease with Progressive Myositis
Year: 2025
Type: article
Study design: Case Report
Abstract: 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.
Source: Journal of Human Immunity
Authors: Ivona Aksentijevich, Dhanya Lakshmi Narayanan, Annemarie Steiner, Shouya Feng, Carl Esperanzate, Iago Pinal-Fernandez, Katja Hrovat, Paul Baker, Gustaf Wigerblad, Mary Maclean, Hongying Wang, Suma Balan, Vaishnavi Badiger, Wenjuan Liu, Sabrina Helmold Hait, William Gahl, Stefania Dell’Orso, Massimo Gadina, Andrew Mammen, Deborah Stone, Daniel Kastner, Mike Rogers, Danica Novacic, Seth Masters
Institutions: National Human Genome Research Institute, Hudson Institute of Medical Research, Walter and Eliza Hall Institute of Medical Research, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kasturba Medical College, Manipal, Nankai University, Garvan Institute of Medical Research
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W4409785991