HDAC7 and Multiple Sclerosis

Histone deacetylase 7 (HDAC7) has emerged as an important modulator in immune regulation, with a protective coding variant implicated in multiple sclerosis. Evidence from large-scale genetic studies supports a strong association between HDAC7 and multiple sclerosis, where a low-frequency variant, c.497G>A (p.Arg166His) (PMID:36516268), was identified as protective against disease. In addition, gene‐based association testing in pediatric-onset multiple sclerosis cohorts strengthened the link between rare coding variation in HDAC7 and disease modulation (PMID:36755464). This convergent genetic evidence, derived from independent patient cohorts, provides critical support for clinical diagnostic decision‑making in the context of complex immune-mediated disorders.

Genetic evidence points to an autosomal contribution whereby the protective variant is seen in low-frequency coding variation. Although traditional segregation data in families is limited for complex traits, the combined case–control studies and gene-based analyses provide robust statistical signal. The recurrence of the variant in distinct patient populations underscores its relevance to multiple sclerosis pathogenesis (PMID:36755464).

Functional assessment studies have elucidated the mechanism by which HDAC7 influences disease risk. Experimental data using transduced regulatory T cells and knock‑in mouse models reveal that the protective variant enhances Treg suppressive capacity and leads to decreased severity in an experimental autoimmune encephalomyelitis model, mirroring findings in patient samples (PMID:36516268). The functional experiments, including transcriptomic analyses and in vivo modeling, demonstrate that modulation of HDAC7 activity directly impacts key immune regulatory pathways relevant to multiple sclerosis.

Further supporting the clinical relevance, complementary functional studies have shown that disruption of HDAC7 in immune cells can lead to dysregulated gene expression, potentially contributing to the immune dysfunction observed in multiple sclerosis. While other studies have evaluated HDAC7 in different disease contexts, none detract from the evidence supporting its specific role in modulating multiple sclerosis risk. Thus, the integrated genetic and experimental findings offer a coherent narrative that reinforces the gene-disease association strength.

Collectively, the convergence of genetic association data and functional experimental evidence highlights a strong role for HDAC7 in modifying multiple sclerosis risk. The protective effect of the c.497G>A (p.Arg166His) variant not only underscores the gene’s critical function in regulatory T cell biology but also points to potential therapeutic avenues for disease modulation. Additional evidence exists that further refines the pathogenic mechanism, surpassing typical ClinGen scoring maximums.

Key take‑home sentence: HDAC7 stands out as a robust genetic determinant in multiple sclerosis, with its protective coding variant offering promising implications for immune‑targeted therapeutic strategies.

References

• Science translational medicine • 2022 • A multiple sclerosis‑protective coding variant reveals an essential role for HDAC7 in regulatory T cells PMID:36516268
• Multiple sclerosis (Houndmills, Basingstoke, England) • 2023 • Rare and low‑frequency coding genetic variants contribute to pediatric‑onset multiple sclerosis PMID:36755464

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