Kcna2, encoding the Kv1.2 potassium voltage-gated channel subunit, is highly expressed in the central and peripheral nervous systems [1]. Kv1.2 channels regulate neuronal excitability, playing a crucial role in the electrical activity of neurons [3]. They are directly involved in the mechanisms related to various neurological functions and diseases [4]. Genetic models, such as gene knockout (KO) or conditional knockout (CKO) mouse models, can be valuable for studying Kcna2's functions.

Functional studies using a Xenopus oocyte two-microelectrode voltage-clamp system on patients with Kcna2 mutations showed that different types of mutations (loss-of-function, gain-of-function, and gain-and-loss-of-function) led to distinct phenotypic features in epileptic encephalopathy. Loss-of-function mutations were associated with predominant focal seizures and prominent sleep-activated epileptic discharges, while gain-of-function mutations were related to more severe epilepsy, developmental problems, ataxia, and brain atrophy. Patients with gain-and-loss-of-function mutations had the most severe early-onset phenotypes [2]. Two epilepsy-associated Kcna2 variants at position H310 had opposite effects on Kv1.2 functional expression. The p.H310Y variant caused “dual gain of function” by increasing cell-surface trafficking and activity and abolishing “ball and chain” inactivation, while the p.H310R variant led to “dual loss of function” by diminishing surface levels and inhibiting voltage-dependent channel opening [3].

In conclusion, Kcna2 is essential for regulating neuronal excitability. Studies on Kcna2-related mutations, especially through functional studies similar to those in KO/CKO mouse models, have revealed its role in various neurological diseases, particularly epileptic encephalopathy. Understanding Kcna2's functions provides insights into the mechanisms of these diseases, potentially guiding future therapeutic strategies [1,2,3].

References:

1. Xie, Changning, Kessi, Miriam, Yin, Fei, Peng, Jing. 2024. Roles of KCNA2 in Neurological Diseases: from Physiology to Pathology. In Molecular neurobiology, 61, 8491-8517. doi:10.1007/s12035-024-04120-9. https://pubmed.ncbi.nlm.nih.gov/38517617/

2. Masnada, Silvia, Hedrich, Ulrike B S, Gardella, Elena, Lerche, Holger, Rubboli, Guido. . Clinical spectrum and genotype-phenotype associations of KCNA2-related encephalopathies. In Brain : a journal of neurology, 140, 2337-2354. doi:10.1093/brain/awx184. https://pubmed.ncbi.nlm.nih.gov/29050392/

3. Mínguez-Viñas, Teresa, Prakash, Varsha, Wang, Kaiqian, Gunnarsson, Cecilia, Pantazis, Antonios. 2023. Two epilepsy-associated variants in KCNA2 (KV 1.2) at position H310 oppositely affect channel functional expression. In The Journal of physiology, 601, 5367-5389. doi:10.1113/JP285052. https://pubmed.ncbi.nlm.nih.gov/37883018/

4. Gao, Kai, Lin, Zehong, Wen, Sijia, Jiang, Yuwu. 2022. Potassium channels and epilepsy. In Acta neurologica Scandinavica, 146, 699-707. doi:10.1111/ane.13695. https://pubmed.ncbi.nlm.nih.gov/36225112/