SCN1A

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.{{cite journal | vauthors = Meisler MH, O'Brien JE, Sharkey LM | title = Sodium channel gene family: epilepsy mutations, gene interactions and modifier effects | journal = The Journal of Physiology | volume = 588 | issue = Pt 11 | pages = 1841–1848 | date = June 2010 | pmid = 20351042 | pmc = 2901972 | doi = 10.1113/jphysiol.2010.188482 }}{{cite journal | vauthors = Ogiwara I, Miyamoto H, Morita N, Atapour N, Mazaki E, Inoue I, Takeuchi T, Itohara S, Yanagawa Y, Obata K, Furuichi T, Hensch TK, Yamakawa K | title = Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation | journal = The Journal of Neuroscience | volume = 27 | issue = 22 | pages = 5903–5914 | date = May 2007 | pmid = 17537961 | pmc = 6672241 | doi = 10.1523/JNEUROSCI.5270-06.2007 }} Alternative splicing of exon 5 gives rise to two alternate exons.{{cite journal | vauthors = Tate SK, Depondt C, Sisodiya SM, Cavalleri GL, Schorge S, Soranzo N, Thom M, Sen A, Shorvon SD, Sander JW, Wood NW, Goldstein DB | title = Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 15 | pages = 5507–5512 | date = April 2005 | pmid = 15805193 | pmc = 556232 | doi = 10.1073/pnas.0407346102 | doi-access = free | bibcode = 2005PNAS..102.5507T }} SCN1A contains a poison exon within intron 20.{{cite journal | vauthors = Carvill GL, Engel KL, Ramamurthy A, Cochran JN, Roovers J, Stamberger H, Lim N, Schneider AL, Hollingsworth G, Holder DH, Regan BM, Lawlor J, Lagae L, Ceulemans B, Bebin EM, Nguyen J, Barsh GS, Weckhuysen S, Meisler M, Berkovic SF, De Jonghe P, Scheffer IE, Myers RM, Cooper GM, Mefford HC | title = Aberrant Inclusion of a Poison Exon Causes Dravet Syndrome and Related SCN1A-Associated Genetic Epilepsies | journal = American Journal of Human Genetics | volume = 103 | issue = 6 | pages = 1022–1029 | date = December 2018 | pmid = 30526861 | pmc = 6288405 | doi = 10.1016/j.ajhg.2018.10.023 }} 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.{{cite journal | vauthors = Long YS, Zhao QH, Su T, Cai YL, Zeng Y, Shi YW, Yi YH, Chang HH, Liao WP | title = 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 = Journal of Neuroscience Research | volume = 86 | issue = 15 | pages = 3375–3381 | date = November 2008 | pmid = 18655196 | doi = 10.1002/jnr.21790 | s2cid = 33673297 }}

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.{{cite journal | vauthors = Goldin AL, Snutch T, Lübbert H, Dowsett A, Marshall J, Auld V, Downey W, Fritz LC, Lester HA, Dunn R | title = Messenger RNA coding for only the alpha subunit of the rat brain Na channel is sufficient for expression of functional channels in Xenopus oocytes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 19 | pages = 7503–7507 | date = October 1986 | pmid = 2429308 | pmc = 386747 | doi = 10.1073/pnas.83.19.7503 | doi-access = free | bibcode = 1986PNAS...83.7503G }} Brain sodium channel alpha subunits form a gene subfamily with several structurally distinct isoforms clustering on chromosome 2q24, types I, II (Na_v1.2), and III (Na_v1.3). There are also several distinct sodium channel alpha subunit isoforms in skeletal and cardiac muscle (Na_v1.4{{cite journal | vauthors = George AL, Komisarof J, Kallen RG, Barchi RL | title = Primary structure of the adult human skeletal muscle voltage-dependent sodium channel | journal = Annals of Neurology | volume = 31 | issue = 2 | pages = 131–137 | date = February 1992 | pmid = 1315496 | doi = 10.1002/ana.410310203 | s2cid = 37892568 }} and Na_v1.5,{{cite journal | vauthors = Gellens ME, George AL, Chen LQ, Chahine M, Horn R, Barchi RL, Kallen RG | title = Primary structure and functional expression of the human cardiac tetrodotoxin-insensitive voltage-dependent sodium channel | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 2 | pages = 554–558 | date = January 1992 | pmid = 1309946 | pmc = 48277 | doi = 10.1073/pnas.89.2.554 | doi-access = free | bibcode = 1992PNAS...89..554G }} 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 Na_V1.1. 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.{{cite journal | vauthors = Escayg A, MacDonald BT, Meisler MH, Baulac S, Huberfeld G, An-Gourfinkel I, Brice A, LeGuern E, Moulard B, Chaigne D, Buresi C, Malafosse A | title = Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2 | journal = Nature Genetics | volume = 24 | issue = 4 | pages = 343–345 | date = April 2000 | pmid = 10742094 | doi = 10.1038/74159 }} 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'.{{cite journal | vauthors = Lossin C | title = A catalog of SCN1A variants | journal = Brain & Development | volume = 31 | issue = 2 | pages = 114–130 | date = February 2009 | pmid = 18804930 | doi = 10.1016/j.braindev.2008.07.011 }} There are 900 distinct mutations reported for the SCN1A gene, approximately half of the reported mutations are truncations which result in no protein.{{cite journal | vauthors = Fujiwara T, Sugawara T, Mazaki-Miyazaki E, Takahashi Y, Fukushima K, Watanabe M, Hara K, Morikawa T, Yagi K, Yamakawa K, Inoue Y | title = Mutations of sodium channel alpha subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic-clonic seizures | journal = Brain | volume = 126 | issue = Pt 3 | pages = 531–546 | date = March 2003 | pmid = 12566275 | doi = 10.1093/brain/awg053 }}{{cite journal | vauthors = Ohmori I, Kahlig KM, Rhodes TH, Wang DW, George AL | title = Nonfunctional SCN1A is common in severe myoclonic epilepsy of infancy | journal = Epilepsia | volume = 47 | issue = 10 | pages = 1636–1642 | date = October 2006 | pmid = 17054685 | doi = 10.1111/j.1528-1167.2006.00643.x }} 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.

Subtle differences in voltage-gated sodium ion channels can have devastating physiological effects and underlie abnormal neurological functioning.{{cite journal | vauthors = Kohrman DC, Smith MR, Goldin AL, Harris J, Meisler MH | title = A missense mutation in the sodium channel Scn8a is responsible for cerebellar ataxia in the mouse mutant jolting | journal = The Journal of Neuroscience | volume = 16 | issue = 19 | pages = 5993–5999 | date = October 1996 | pmid = 8815882 | pmc = 6579185 | doi = 10.1523/JNEUROSCI.16-19-05993.1996 }}{{cite journal | vauthors = Bulman DE | title = Phenotype variation and newcomers in ion channel disorders | journal = Human Molecular Genetics | volume = 6 | issue = 10 | pages = 1679–1685 | date = 1997 | pmid = 9300659 | doi = 10.1093/hmg/6.10.1679 }} 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). 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.{{cite journal | vauthors = Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P | title = De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy | journal = American Journal of Human Genetics | volume = 68 | issue = 6 | pages = 1327–1332 | date = June 2001 | pmid = 11359211 | pmc = 1226119 | doi = 10.1086/320609 }} There are currently two databases on SCN1A mutations.{{cite web | title = The Variation Database of SCN1A | url = http://www.molgen.ua.ac.be/SCN1AMutations/ | archive-url = https://web.archive.org/web/20171007043647/http://www.molgen.ua.ac.be/SCN1AMutations/ | archive-date = 7 October 2017 | publisher = Vlaams Instituut voor Biotechnologie (VIB) | work = Department of Molecular Genetics }}{{cite web | title = The SCN1A gene homepage | url = https://databases.lovd.nl/shared/genes/SCN1A | work = Leiden Open Variation Database (LOVD) | publisher = Leiden University Medical Center }}

Mice with knock-in SCN1A mutations, who are model organisms for DS quickly develop seizures, indicative of a significant reduction in the function of Na_V1.1. It has been hypothesized that reduced sodium currents due to Na_V1.1 mutations may cause hypoexcitability in GABAergic inhibitory interneurons leading to epilepsy. 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.{{cite journal | vauthors = Yu FH, Mantegazza M, Westenbroek RE, Robbins CA, Kalume F, Burton KA, Spain WJ, McKnight GS, Scheuer T, Catterall WA | title = Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy | journal = Nature Neuroscience | volume = 9 | issue = 9 | pages = 1142–1149 | date = September 2006 | pmid = 16921370 | doi = 10.1038/nn1754 }}

Mutations in the SCN1A gene cause inherited febrile seizures, GEFS+, type 2, and Dravet syndrome.{{cite journal | vauthors = Escayg A, MacDonald BT, Meisler MH, Baulac S, Huberfeld G, An-Gourfinkel I, Brice A, LeGuern E, Moulard B, Chaigne D, Buresi C, Malafosse A | title = Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2 | journal = Nature Genetics | volume = 24 | issue = 4 | pages = 343–345 | date = April 2000 | pmid = 10742094 | doi = 10.1038/74159 | s2cid = 29543172 }}{{cite journal | vauthors = Spampanato J, Escayg A, Meisler MH, Goldin AL | title = Functional effects of two voltage-gated sodium channel mutations that cause generalized epilepsy with febrile seizures plus type 2 | journal = The Journal of Neuroscience | volume = 21 | issue = 19 | pages = 7481–7490 | date = October 2001 | pmid = 11567038 | pmc = 6762922 | doi = 10.1523/jneurosci.21-19-07481.2001 }}{{cite journal | vauthors = Nabbout R, Gennaro E, Dalla Bernardina B, Dulac O, Madia F, Bertini E, Capovilla G, Chiron C, Cristofori G, Elia M, Fontana E, Gaggero R, Granata T, Guerrini R, Loi M, La Selva L, Lispi ML, Matricardi A, Romeo A, Tzolas V, Valseriati D, Veggiotti P, Vigevano F, Vallée L, Dagna Bricarelli F, Bianchi A, Zara F | title = Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy | journal = Neurology | volume = 60 | issue = 12 | pages = 1961–1967 | date = June 2003 | pmid = 12821740 | doi = 10.1212/01.wnl.0000069463.41870.2f | s2cid = 604240 }}{{cite web | url = http://www.scn1a.info/ | title = SCN1A infobase | author = Lossin C | quote = compilation of genetic variations in the SCN1A gene that alter the expression or function of Nav1.1 | access-date = 2009-10-30 }}

On 29 November 2008, The Sydney Morning Herald reported the first evidence of private intellectual property rights over human DNA{{cite web | url = http://www.smh.com.au/news/national/sick-babies-denied-treatment-in-row/2008/11/28/1227491827171.html | title = Sick babies denied treatment in DNA row – | author = Robotham J | date = 29 November 2008 | work = National News | publisher = Sidney Morning Herald – smh.com.au | access-date = 2008-12-03}} 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.

Na_v1.1 has been shown to interact with syntrophin, alpha 1.{{cite journal | vauthors = Gee SH, Madhavan R, Levinson SR, Caldwell JH, Sealock R, Froehner SC | title = Interaction of muscle and brain sodium channels with multiple members of the syntrophin family of dystrophin-associated proteins | journal = The Journal of Neuroscience | volume = 18 | issue = 1 | pages = 128–137 | date = January 1998 | pmid = 9412493 | pmc = 6793384 | doi = 10.1523/jneurosci.18-01-00128.1998 }}

• Sodium channel

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{{refbegin|30em}}

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• {{cite journal | vauthors = Escayg A, Heils A, MacDonald BT, Haug K, Sander T, Meisler MH | title = A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus--and prevalence of variants in patients with epilepsy | journal = American Journal of Human Genetics | volume = 68 | issue = 4 | pages = 866–873 | date = April 2001 | pmid = 11254445 | pmc = 1275640 | doi = 10.1086/319524 }}
• {{cite journal | vauthors = Whitaker WR, Faull RL, Waldvogel HJ, Plumpton CJ, Emson PC, Clare JJ | title = Comparative distribution of voltage-gated sodium channel proteins in human brain | journal = Brain Research. Molecular Brain Research | volume = 88 | issue = 1–2 | pages = 37–53 | date = March 2001 | pmid = 11295230 | doi = 10.1016/S0169-328X(00)00289-8 }}
• {{cite journal | vauthors = Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P | title = De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy | journal = American Journal of Human Genetics | volume = 68 | issue = 6 | pages = 1327–1332 | date = June 2001 | pmid = 11359211 | pmc = 1226119 | doi = 10.1086/320609 }}
• {{cite journal | vauthors = Sugawara T, Mazaki-Miyazaki E, Ito M, Nagafuji H, Fukuma G, Mitsudome A, Wada K, Kaneko S, Hirose S, Yamakawa K | title = Nav1.1 mutations cause febrile seizures associated with afebrile partial seizures | journal = Neurology | volume = 57 | issue = 4 | pages = 703–705 | date = August 2001 | pmid = 11524484 | doi = 10.1212/wnl.57.4.703 | s2cid = 45138036 }}
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• {{cite journal | vauthors = Ito M, Nagafuji H, Okazawa H, Yamakawa K, Sugawara T, Mazaki-Miyazaki E, Hirose S, Fukuma G, Mitsudome A, Wada K, Kaneko S | title = Autosomal dominant epilepsy with febrile seizures plus with missense mutations of the (Na+)-channel alpha 1 subunit gene, SCN1A | journal = Epilepsy Research | volume = 48 | issue = 1–2 | pages = 15–23 | date = January 2002 | pmid = 11823106 | doi = 10.1016/S0920-1211(01)00313-8 | s2cid = 25555020 }}

{{refend}}

• [https://www.ncbi.nlm.nih.gov/books/NBK1388/ GeneReviews/NCBI/NIH/UW entry on Familial Hemiplegic Migraine]
• [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=gefs GeneReviews/NCBI/NIH/UW entry on SCN1A-Related Seizure Disorders]
• {{MeshName|SCN1A+protein,+human}}

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{{Ion channels|g2}}

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Category:Sodium channels