CACNA1H

WHAT IS cacna1h?

CACNA1H is a gene located on the short arm of chromosome 16 at position 13.3 and encodes the pore-forming alpha subunit of the T-type, low voltage–activated calcium channel (CaV3.2). The relationship between genetic variation in the gene CACNA1H and childhood absence epilepsy is well established. Gain-of-function mutations in CACNA1H have also been associated with primary aldosteronism while loss-of-function mutations have been reported in autism spectrum disorders, amyotrophic lateral sclerosis (ALS), and congenital amyotrophy.

Reported pathogenic CACNA1H variants are primarily missense, meaning that there is a substitution in which the nucleotide change results in the replacement of one protein building block (amino acid) with another in the protein made from the gene. The amino acid change may alter the function of the protein.

Most recently, research has identified CACNA1H as a genetic modifier of epilepsy, specifically with the expression of CACNA1A and SCN8A variants. While additional studies are required to uncover the detailed underlying pathogenic mechanisms of these variants, the current findings support that variants in CACNA1H contribute to the etiology of epilepsy, including developmental and epileptic encephalopathies (DEEs).

References

Heron, S. E., Khosravani, H., Varela, D., Bladen, C., Williams, T. C., Newman, M. R., Scheffer, I. E., Berkovic, S. F., Mulley, J. C., & Zamponi, G. W. (2007). Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants. Annals of Neurology, 62(6), 560–568.

Liang, J., Zhang, Y., Chen, Y., Wang, J., Pan, H., Wu, H., Xu, K., Liu, X., Jiang, Y., & Shen, Y. (2006). Common Polymorphisms in the CACNA1H Gene Associated with Childhood Absence Epilepsy in Chinese Han Population. Annals of Human Genetics, 71, 325–335.

Miao, Q. L., Herlitze, S., Mark, M. D., & Noebels, J. L. (2019). Adult loss of Cacna1a in mice recapitulates childhood absence epilepsy by distinct thalamic bursting mechanisms. Brain, 143(1), 161–174. https://doi.org/10.1093/brain/awz365

Stringer, R. N., Jurkovicova-Tarabova, B., Huang, S., Haji-Ghassemi, O., Idoux, R., Liashenko, A., Souza, I. A., Rzhepetskyy, Y., Lacinova, L., van Petegem, F., Zamponi, G. W., Pamphlett, R., & Weiss, N. (2020). A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity. Molecular Brain, 13(1). https://doi.org/10.1186/s13041-020-00577-6

Stringer, R. N., Jurkovicova-Tarabova, B., Souza, I. A., Ibrahim, J., Vacik, T., Fathalla, W. M., Hertecant, J., Zamponi, G. W., Lacinova, L., & Weiss, N. (2021). De novo SCN8A and inherited rare CACNA1H variants associated with severe developmental and epileptic encephalopathy. Molecular Brain, 14(1). https://doi.org/10.1186/s13041-021-00838-y