Kcna3, encoding for Kv1.3 subunits, is a mammalian homologue of the Drosophila shaker family. The Kv1.3 channels it codes for are involved in regulating potassium flux, which is crucial for calcium-mediated signaling in cells like CD4+ T-cells. It is also implicated in immunomodulation of autoreactive effector and memory T-cell-mediated autoimmune diseases [3,6].

De novo missense variants in KCNA3 are associated with Developmental and Epileptic Encephalopathies (DEEs), presenting with speech delay, motor delay, intellectual disability, epilepsy, and autism spectrum disorder. Functional analysis of Kv1.3 channels carrying these variants shows heterogeneous functional changes, including loss-of-function and mixed loss-and gain-of-function effects [2]. A common genetic variant rs2821557 in KCNA3 is linked to the severity of multiple sclerosis, likely due to enhanced Kv1.3-mediated accumulation of pathogenic CXCR3+ TEM cells and exacerbated neuroinflammation [4]. Also, methylation of KCNA3 is identified as a promising diagnostic marker for esophageal squamous cell carcinoma and can be used in a non-invasive blood-based methylation assay for esophageal cancer detection [1,5].

In conclusion, Kcna3 plays a vital role in neural development and immune-related processes. Studies on its variants and methylation states have revealed its significance in diseases such as DEEs, multiple sclerosis, and esophageal cancer. These findings contribute to a better understanding of the disease mechanisms and potentially offer new diagnostic and therapeutic strategies.