TOMM70 and COVID‑19 Susceptibility

Recent multi‑patient studies have highlighted TOMM70 as a candidate gene in the context of COVID‑19 (PMID:34530086, PMID:38902252). Although direct genetic evidence from large cohorts or familial segregation analyses is limited, TOMM70 is recurrently identified as part of the SARS‑CoV‑2 host interactome. In these studies, TOMM70 was nominated based on protein‑protein interaction data and computational models predicting its potential role in viral pathogenicity and immune modulation. The evidence supports an association where TOMM70 may influence disease susceptibility by its involvement in mitochondrial import processes and the modulation of type I interferon responses. However, the absence of multiple unrelated probands or extensive segregation data limits conclusive genetic correlation with COVID‑19. Additional investigations are required to better define the penetrance and expressivity of candidate variants in this gene.

Functional studies provide further insight into the biological plausibility of this association. Biophysical assessments have shown that TOMM70 engages with SARS‑CoV‑2 Orf9b, a viral accessory protein, which in turn may suppress the interferon response by altering the receptor's conformational dynamics (PMID:40027672, PMID:20504278). These experimental studies have characterized features such as the monomeric functional state of TOMM70 and the impact of lipid binding on its structure. Although a representative pathogenic variant (e.g., c.794C>T (p.Thr265Met)) has been reported in the context of mitochondrial disease, its candidacy in COVID‑19 has not been directly validated. Overall, the mechanistic data provide moderate functional support, even if the genetic evidence remains limited.

References

• Gene • 2022 • An overview of human proteins and genes involved in SARS‑CoV‑2 infection PMID:34530086
• Scientific reports • 2024 • Predicting human and viral protein variants affecting COVID‑19 susceptibility and repurposing therapeutics PMID:38902252
• The Journal of biological chemistry • 2006 • Tracking the unfolding pathway of a multirepeat protein via tryptophan scanning: evidence of localized instability in the mitochondrial import receptor Tom70 PMID:16803880
• The Biochemical journal • 2010 • Human mitochondrial import receptor Tom70 functions as a monomer PMID:20504278
• bioRxiv : the preprint server for biology • 2025 • Coupled equilibria of dimerization and lipid binding modulate SARS Cov 2 Orf9b interactions and interferon response PMID:40027672

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