KCNA3, encoding for Kv1.3 subunits, is a mammalian homologue of the Drosophila shaker family. The Kv1.3 potassium channel it encodes is involved in various biological processes, including immunomodulation, T-cell activation, and ion flux regulation. It may participate in signaling pathways related to lymphocyte function and is important for robust calcium influx in T cells [6,7].

De novo missense variants in KCNA3 have been associated with developmental and epileptic encephalopathy (DEE). Functional analysis of Kv1.3 channels carrying these variants revealed 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 [3]. Polymorphisms in KCNA3 are associated with susceptibility to autoimmune pancreatitis in the Japanese population, suggesting its role in the etiology of this disease [5]. Also, hypermethylation of KCNA3 in circulating cell-free DNA shows promise as a non-invasive diagnostic marker for esophageal cancer, with a methylation-based assay demonstrating high diagnostic accuracy [1,4].

In conclusion, KCNA3 is crucial for normal physiological function, especially in the context of the immune and nervous systems. Research using genetic models, although not explicitly KO/CKO mouse models in the provided references, has revealed its significance in DEE, multiple sclerosis, autoimmune pancreatitis, and esophageal cancer. Understanding KCNA3's role provides insights into disease mechanisms and potential diagnostic and therapeutic strategies for these conditions.

References:

1. Bian, Yan, Gao, Ye, Lin, Han, Li, Zhaoshen, Wang, Luowei. 2024. Non-invasive diagnosis of esophageal cancer by a simplified circulating cell-free DNA methylation assay targeting OTOP2 and KCNA3: a double-blinded, multicenter, prospective study. In Journal of hematology & oncology, 17, 47. doi:10.1186/s13045-024-01565-2. https://pubmed.ncbi.nlm.nih.gov/38890756/

2. Soldovieri, Maria Virginia, Ambrosino, Paolo, Mosca, Ilaria, Taglialatela, Maurizio, Lemke, Johannes R. 2023. De novo variants in KCNA3 cause developmental and epileptic encephalopathy. In Annals of neurology, 95, 365-376. doi:10.1002/ana.26826. https://pubmed.ncbi.nlm.nih.gov/37964487/

3. Lioudyno, Victoria, Abdurasulova, Irina, Negoreeva, Irina, Klimenko, Victor, Lioudyno, Maria. 2020. A common genetic variant rs2821557 in KCNA3 is linked to the severity of multiple sclerosis. In Journal of neuroscience research, 99, 200-208. doi:10.1002/jnr.24596. https://pubmed.ncbi.nlm.nih.gov/32056271/

4. Bian, Yan, Gao, Ye, Lu, Chaojing, Chen, Hezhong, Wang, Luowei. 2023. Genome-wide methylation profiling identified methylated KCNA3 and OTOP2 as promising diagnostic markers for esophageal squamous cell carcinoma. In Chinese medical journal, 137, 1724-1735. doi:10.1097/CM9.0000000000002832. https://pubmed.ncbi.nlm.nih.gov/37650127/

5. Ota, Masao, Ito, Tetsuya, Umemura, Takeji, Hamano, Hideaki, Kawa, Shigeyuki. . Polymorphism in the KCNA3 gene is associated with susceptibility to autoimmune pancreatitis in the Japanese population. In Disease markers, 31, 223-9. doi:10.3233/DMA-2011-0820. https://pubmed.ncbi.nlm.nih.gov/22045429/

6. Kang, Jung-Ah, Park, Sang-Heon, Jeong, Sang Phil, Park, Chul-Seung, Park, Sung-Gyoo. 2016. Epigenetic regulation of Kcna3-encoding Kv1.3 potassium channel by cereblon contributes to regulation of CD4+ T-cell activation. In Proceedings of the National Academy of Sciences of the United States of America, 113, 8771-6. doi:10.1073/pnas.1502166113. https://pubmed.ncbi.nlm.nih.gov/27439875/

7. Hosseinzadeh, Zohreh, Warsi, Jamshed, Elvira, Bernat, Shumilina, Ekaterina, Lang, Florian. 2015. Up-regulation of Kv1.3 channels by janus kinase 2. In The Journal of membrane biology, 248, 309-17. doi:10.1007/s00232-015-9772-2. https://pubmed.ncbi.nlm.nih.gov/25644777/