Sodium channel protein type 1 subunit alpha (SCN1A), is a protein which in humans is encoded by the SCN1Agene.[5][6][7][8]
Gene location
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.[9][10] Alternative splicing of exon 5 gives rise to two alternate exons.[11]SCN1A contains a poison exon within intron 20.[12] The promoter has been identified 2.5 kilobase pairs 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.[13]
Function
The vertebrate sodium channel is a voltage-gated ion channel essential for the generation and propagation of action potentials, chiefly in nerve and muscle. Voltage-sensitive sodium channels are heteromeric complexes consisting of a large central pore-forming glycosylated alpha subunit and 2 smaller auxiliary beta subunits. Functional studies have indicated that the transmembrane alpha subunit of the brain sodium channels is sufficient for expression of functional sodium channels.[14] Brain sodium channel alpha subunits form a gene subfamily with several structurally distinct isoforms clustering on chromosome 2q24, types I, II (Nav1.2), and III (Nav1.3). There are also several distinct sodium channel alpha subunit isoforms in skeletal and cardiac muscle (Nav1.4[15] and Nav1.5,[16] respectively).
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.[17] 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'.[18] There are 900 distinct mutations reported for the SCN1A gene, approximately half of the reported mutations are truncations which result in no protein.[19][20] 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.[9]
Subtle differences in voltage-gated sodium ion channels can have devastating physiological effects and underlie abnormal neurological functioning.[21][22] Mutations to the SCN1A gene most often result 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).[19] 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.[23] There are currently two databases on SCN1A mutations.[24][25]
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.[10] It has been hypothesized that reduced sodium currents due to NaV1.1 mutations may cause hypoexcitability in GABAergic inhibitory interneurons leading to epilepsy.[13] 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.[10][13][26]
On 29 November 2008, The Sydney Morning Herald reported the first evidence of private intellectual property rights over human DNA[31] having adversely affected medical care. The Melbourne company Genetic Technologies (GTG) controls rights to the gene, and requires royalties for tests on the gene, which can help identify Dravet syndrome. Doctors on the Children's Hospital in Westmead, Australia have told journalists that they would test 50% more infants for the gene, if they could conduct the test on site.
^Malo MS, Blanchard BJ, Andresen JM, Srivastava K, Chen XN, Li X, et al. (1994). "Localization of a putative human brain sodium channel gene (SCN1A) to chromosome band 2q24". Cytogenetics and Cell Genetics. 67 (3): 178–186. doi:10.1159/000133818. PMID8062593.
^Ito M, Nagafuji H, Okazawa H, Yamakawa K, Sugawara T, Mazaki-Miyazaki E, et al. (January 2002). "Autosomal dominant epilepsy with febrile seizures plus with missense mutations of the (Na+)-channel alpha 1 subunit gene, SCN1A". Epilepsy Research. 48 (1–2): 15–23. doi:10.1016/S0920-1211(01)00313-8. PMID11823106. S2CID25555020.
^Catterall WA, Goldin AL, Waxman SG (December 2005). "International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels". Pharmacological Reviews. 57 (4): 397–409. doi:10.1124/pr.57.4.4. PMID16382098. S2CID7332624.
^ abcLong YS, Zhao QH, Su T, Cai YL, Zeng Y, Shi YW, et al. (November 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. doi:10.1002/jnr.21790. PMID18655196. S2CID33673297.
^Escayg A, MacDonald BT, Meisler MH, Baulac S, Huberfeld G, An-Gourfinkel I, et al. (April 2000). "Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2". Nature Genetics. 24 (4): 343–345. doi:10.1038/74159. PMID10742094.
^ abFujiwara T, Sugawara T, Mazaki-Miyazaki E, Takahashi Y, Fukushima K, Watanabe M, et al. (March 2003). "Mutations of sodium channel alpha subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic-clonic seizures". Brain. 126 (Pt 3): 531–546. doi:10.1093/brain/awg053. PMID12566275.
^Ohmori I, Kahlig KM, Rhodes TH, Wang DW, George AL (October 2006). "Nonfunctional SCN1A is common in severe myoclonic epilepsy of infancy". Epilepsia. 47 (10): 1636–1642. doi:10.1111/j.1528-1167.2006.00643.x. PMID17054685.
^Bulman DE (1997). "Phenotype variation and newcomers in ion channel disorders". Human Molecular Genetics. 6 (10): 1679–1685. doi:10.1093/hmg/6.10.1679. PMID9300659.
^Yu FH, Mantegazza M, Westenbroek RE, Robbins CA, Kalume F, Burton KA, et al. (September 2006). "Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy". Nature Neuroscience. 9 (9): 1142–1149. doi:10.1038/nn1754. PMID16921370.
^Escayg A, MacDonald BT, Meisler MH, Baulac S, Huberfeld G, An-Gourfinkel I, et al. (April 2000). "Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2". Nature Genetics. 24 (4): 343–345. doi:10.1038/74159. PMID10742094. S2CID29543172.
^Nabbout R, Gennaro E, Dalla Bernardina B, Dulac O, Madia F, Bertini E, et al. (June 2003). "Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy". Neurology. 60 (12): 1961–1967. doi:10.1212/01.wnl.0000069463.41870.2f. PMID12821740. S2CID604240.
^Lossin C. "SCN1A infobase". Retrieved 30 October 2009. compilation of genetic variations in the SCN1A gene that alter the expression or function of Nav1.1
Lerche H, Jurkat-Rott K, Lehmann-Horn F (2001). "Ion channels and epilepsy". American Journal of Medical Genetics. 106 (2): 146–159. doi:10.1002/ajmg.1582. PMID11579435.
Kanai K, Hirose S, Oguni H, Fukuma G, Shirasaka Y, Miyajima T, et al. (July 2004). "Effect of localization of missense mutations in SCN1A on epilepsy phenotype severity". Neurology. 63 (2): 329–334. doi:10.1212/01.wnl.0000129829.31179.5b. PMID15277629. S2CID36070893.
Oguni H, Hayashi K, Osawa M, Awaya Y, Fukuyama Y, Fukuma G, et al. (2004). "Severe myoclonic epilepsy in infancy: clinical analysis and relation to SCN1A mutations in a Japanese cohort". Advances in Neurology. 95: 103–117. PMID15508916.
Malo MS, Blanchard BJ, Andresen JM, Srivastava K, Chen XN, Li X, et al. (1994). "Localization of a putative human brain sodium channel gene (SCN1A) to chromosome band 2q24". Cytogenetics and Cell Genetics. 67 (3): 178–186. doi:10.1159/000133818. PMID8062593.
Sugawara T, Mazaki-Miyazaki E, Ito M, Nagafuji H, Fukuma G, Mitsudome A, et al. (August 2001). "Nav1.1 mutations cause febrile seizures associated with afebrile partial seizures". Neurology. 57 (4): 703–705. doi:10.1212/wnl.57.4.703. PMID11524484. S2CID45138036.
Abou-Khalil B, Ge Q, Desai R, Ryther R, Bazyk A, Bailey R, et al. (December 2001). "Partial and generalized epilepsy with febrile seizures plus and a novel SCN1A mutation". Neurology. 57 (12): 2265–2272. doi:10.1212/wnl.57.12.2265. PMID11756608. S2CID26448714.
Ito M, Nagafuji H, Okazawa H, Yamakawa K, Sugawara T, Mazaki-Miyazaki E, et al. (January 2002). "Autosomal dominant epilepsy with febrile seizures plus with missense mutations of the (Na+)-channel alpha 1 subunit gene, SCN1A". Epilepsy Research. 48 (1–2): 15–23. doi:10.1016/S0920-1211(01)00313-8. PMID11823106. S2CID25555020.
