Kcnc2-KO Mouse

Kcnc2 encodes Kv3.2, a member of the voltage-gated potassium channel subfamily. It is crucial for the generation of fast-spiking properties in cortical GABAergic interneurons, which is pivotal to maintaining the excitation/inhibition balance in mammalian brains [2].

Recently, de novo variants in Kcnc2 have been associated with various forms of epilepsy, including genetic generalized epilepsy (GGE) and developmental and epileptic encephalopathy (DEE) [1,2,4,5,6,7]. Functional studies on variants in Kcnc2, such as patch-clamp techniques in HEK293 cells and Xenopus laevis oocytes, have shown changes in current amplitude, activation, and deactivation kinetics of the channel [1,2,4]. These changes can lead to either gain-of-function or loss-of-function effects, ultimately disinhibiting neural networks and impairing neuronal excitability [2,3,8].

In conclusion, Kcnc2 plays an essential role in regulating the fast-spiking properties of GABAergic interneurons and maintaining brain excitation/inhibition balance. The discovery of its association with epilepsy through functional studies of its variants provides important insights into the pathogenesis of epilepsy, suggesting that Kcnc2 could be a potential target for epilepsy treatment [1,2,4].

References:

1. Seiffert, Simone, Pendziwiat, Manuela, Hedrich, Ulrike B S, Weber, Yvonne, Schwarz, Niklas. 2023. KCNC2 variants of uncertain significance are also associated to various forms of epilepsy. In Frontiers in neurology, 14, 1212079. doi:10.3389/fneur.2023.1212079. https://pubmed.ncbi.nlm.nih.gov/37360341/

2. Li, Lin, Liu, Zili, Yang, Haiyang, Hu, Jun, Shen, Xuefeng. 2022. Investigation of novel de novo KCNC2 variants causing severe developmental and early-onset epileptic encephalopathy. In Seizure, 101, 218-224. doi:10.1016/j.seizure.2022.09.004. https://pubmed.ncbi.nlm.nih.gov/36087422/

3. Clatot, Jerome, Currin, Christopher B, Liang, Qiansheng, Covarrubias, Manuel, Goldberg, Ethan M. 2024. A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2307776121. doi:10.1073/pnas.2307776121. https://pubmed.ncbi.nlm.nih.gov/38194456/

4. Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Helbig, Ingo, Weber, Yvonne. 2022. Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants. In Neurology, 98, e2046-e2059. doi:10.1212/WNL.0000000000200660. https://pubmed.ncbi.nlm.nih.gov/35314505/

5. Wang, Sumei, Yu, Yejing, Wang, Xu, Gu, Weiyue, Sun, Dan. 2022. Emerging evidence of genotype-phenotype associations of developmental and epileptic encephalopathy due to KCNC2 mutation: Identification of novel R405G. In Frontiers in molecular neuroscience, 15, 950255. doi:10.3389/fnmol.2022.950255. https://pubmed.ncbi.nlm.nih.gov/36090251/

6. Vetri, Luigi, Calì, Francesco, Vinci, Mirella, Romano, Valentino, Elia, Maurizio. 2020. A de novo heterozygous mutation in KCNC2 gene implicated in severe developmental and epileptic encephalopathy. In European journal of medical genetics, 63, 103848. doi:10.1016/j.ejmg.2020.103848. https://pubmed.ncbi.nlm.nih.gov/31972370/

7. Rydzanicz, Małgorzata, Zwoliński, Piotr, Gasperowicz, Piotr, Konarzewska, Magdalena, Płoski, Rafał. 2021. A recurrent de novo variant supports KCNC2 involvement in the pathogenesis of developmental and epileptic encephalopathy. In American journal of medical genetics. Part A, 185, 3384-3389. doi:10.1002/ajmg.a.62455. https://pubmed.ncbi.nlm.nih.gov/34448338/

8. Mukherjee, Souhrid, Cassini, Thomas A, Hu, Ningning, Phillips, John A, Capra, John A. 2022. Personalized structural biology reveals the molecular mechanisms underlying heterogeneous epileptic phenotypes caused by de novo KCNC2 variants. In HGG advances, 3, 100131. doi:10.1016/j.xhgg.2022.100131. https://pubmed.ncbi.nlm.nih.gov/36035247/