SCN1A (gene)
The SCN1A gene is located on chromosome 2 of humans, and is made up of 26 exons spanning a total length of 6030 nucleotide base pairs (bp).[1][2] Alternative splicing of exon 5 gives rise to two alternate exons.[3] The promoter has been identified 2.5 kilobase pairs (kb) upstream of the transcription start site, and the 5’- untranslated exons may enhance expression of the SCN1A gene in SH-SY5Y cells, a human cell line derived from a neuroblastoma.[4]
The SCN1A gene codes for the alpha subunit of the voltage-gated sodium ion channel making it a member of ten paralogous gene families which code for the voltage-gated sodium transmembrane proteins NaV1.1. Within the family of genes which code for other portions of voltage-gated sodium channels, the SCN1A mutations were the first identified, since mutations to this gene caused epilepsy and febrile seizures.[5] Indeed, the SCN1A gene is one of the most commonly mutated genes in the human genome associated with epilepsy, which has given it the title of a ‘super culprit gene’.[6] There are 900 distinct mutations reported for the SCN1A gene, approximately half of the reported mutations are truncations which result in no protein.[7][8] The remaining half of mutations are missense mutations, which are predicted to either cause loss-of-function or gain-of-function, though very few have been tested for functionality in the lab.[1]
Subtle differences in voltage-gated sodium ion channels can have devastating physiological effects and underlie abnormal neurological functioning.[9][10] Mutations to the SCN1A gene most often results in different forms of seizure disorders, the most common forms of seizure disorders are Dravet Syndrome (DS), Intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTC), and severe myoclonic epilepsy borderline (SMEB).[7] Clinically, 70-80% of patients with DS have identified mutations specific to the SCN1A gene, which are caused by de novo heterozygous mutations of the SCN1A gene[11] There are currently two databases on SCN1A mutations, Infobase and the SCN1A variant database.
Mice with knock-in SCN1A mutations, who are model organisms for DS quickly develop seizures, indicative of a significant reduction in the function of NaV1.1.[2] It has been hypothesized that reduced sodium currents due to NaV1.1 mutations may cause hyper-excitability in GABAergic inhibitory interneurons leading to epilepsy.[4] Mice in both the homozygous and heterozygous states develop the seizure phenotype and ataxia. Though homozygous mice die on average during the second to third week of life and approximately 50% of heterozygous null mice survive into adulthood.[2][4][12]
- From a gene symbol: This is a redirect from a Human Genome Organisation (HUGO) symbol for a gene to an article about the gene.
References
- ↑ 1.0 1.1 Meisler, M. H., O’Brien, J. E., & Sharkey, L. M. (2010). Sodium channel gene family: epilepsy mutations, gene interactions and modifier effects. The Journal of Physiology, 588(11), 1841–1848. https://doi.org/10.1113/jphysiol.2010.188482
- ↑ 2.0 2.1 2.2 Ogiwara, I., Miyamoto, H., Morita, N., Atapour, N., Mazaki, E., Inoue, I., … Yamakawa, K. (2007). Nav1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying an Scn1a Gene Mutation. Journal of Neuroscience, 27(22), 5903–5914. https://doi.org/10.1523/JNEUROSCI.5270-06.2007
- ↑ Tate, S. K., Depondt, C., Sisodiya, S. M., Cavalleri, G. L., Schorge, S., Soranzo, N., … Goldstein, D. B. (2005). Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin. Proceedings of the National Academy of Sciences of the United States of America, 102(15), 5507–5512. https://doi.org/10.1073/pnas.0407346102
- ↑ 4.0 4.1 4.2 Long, Y.-S., Zhao, Q.-H., Su, T., Cai, Y.-L., Zeng, Y., Shi, Y.-W., … Liao, W.-P. (2008). Identification of the promoter region and the 5′-untranslated exons of the human voltage-gated sodium channel Nav1.1 gene (SCN1A) and enhancement of gene expression by the 5′-untranslated exons. Journal of Neuroscience Research, 86(15), 3375–3381. https://doi.org/10.1002/jnr.21790
- ↑ Escayg, A., MacDonald, B. T., Meisler, M. H., Baulac, S., Huberfeld, G., An-Gourfinkel, I., … Malafosse, A. (2000). Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nature Genetics, 24(4), 343–345. https://doi.org/10.1038/74159
- ↑ Lossin, C. (2009). A catalog of SCN1A variants. Brain and Development, 31(2), 114–130. https://doi.org/10.1016/j.braindev.2008.07.011
- ↑ 7.0 7.1 Fujiwara, T., Sugawara, T., Mazaki‐Miyazaki, E., Takahashi, Y., Fukushima, K., Watanabe, M., … Inoue, Y. (2003). Mutations of sodium channel α subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic–clonic seizures. Brain, 126(3), 531–546. https://doi.org/10.1093/brain/awg053
- ↑ Ohmori, I., Kahlig, K. M., Rhodes, T. H., Wang, D. W., & George, A. L. (2006). Nonfunctional SCN1A Is Common in Severe Myoclonic Epilepsy of Infancy. Epilepsia, 47(10), 1636–1642. https://doi.org/10.1111/j.1528-1167.2006.00643.x
- ↑ Kohrman, D. C., Smith, M. R., Goldin, A. L., Harris, J., & Meisler, M. H. (1996). A Missense Mutation in the Sodium Channel Scn8a Is Responsible for Cerebellar Ataxia in the Mouse Mutant jolting. Journal of Neuroscience, 16(19), 5993–5999.
- ↑ Bulman, D. E. (1997). Phenotype Variation and Newcomers in Ion Channel Disorders. Human Molecular Genetics, 6(10), 1679–1685. https://doi.org/10.1093/hmg/6.10.1679
- ↑ Claes, L., Del-Favero, J., Ceulemans, B., Lagae, L., Van Broeckhoven, C., & De Jonghe, P. (2001). De Novo Mutations in the Sodium-Channel Gene SCN1A Cause Severe Myoclonic Epilepsy of Infancy. American Journal of Human Genetics, 68(6), 1327–1332.
- ↑ Yu, F. H., Mantegazza, M., Westenbroek, R. E., Robbins, C. A., Kalume, F., Burton, K. A., … Catterall, W. A. (2006). Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nature Neuroscience, 9(9), 1142–1149. https://doi.org/10.1038/nn1754