Podjedinica alfa proteinskog tipa 1 natrijskog kanala (SCN1A), jest protein koji je kod ljudi kodiran genom SCN1A sa hromosoma 2.[5][6][7][8]

SCN1A
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

7DTD

Identifikatori
AliasiSCN1A
Vanjski ID-jeviOMIM: 182389 MGI: 98246 HomoloGene: 21375 GeneCards: SCN1A
Lokacija gena (čovjek)
Hromosom 2 (čovjek)
Hrom.Hromosom 2 (čovjek)[1]
Hromosom 2 (čovjek)
Genomska lokacija za SCN1A
Genomska lokacija za SCN1A
Bend2q24.3Početak165,984,641 bp[1]
Kraj166,149,214 bp[1]
Lokacija gena (miš)
Hromosom 2 (miš)
Hrom.Hromosom 2 (miš)[2]
Hromosom 2 (miš)
Genomska lokacija za SCN1A
Genomska lokacija za SCN1A
Bend2 C1.3|2 39.13 cMPočetak66,101,122 bp[2]
Kraj66,271,184 bp[2]
Obrazac RNK ekspresije
Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija sodium channel activity
voltage-gated ion channel activity
ion channel activity
voltage-gated sodium channel activity
Ćelijska komponenta voltage-gated sodium channel complex
integral component of membrane
membrana
nukleoplazma
ćelijska membrana
nuclear body
Interkalirani disk
Z discdkac
T-tubule
Akson
Ranvijerov čvor
sodium channel complex
soma
axon initial segment
Biološki proces membrane depolarization during action potential
sodium ion transmembrane transport
regulation of ion transmembrane transport
ion transport
transmembrane transport
ion transmembrane transport
sodium ion transport
cardiac muscle cell action potential involved in contraction
Akcijski potencijal
adult walking behavior
neuronal action potential propagation
neuronal action potential
regulation of membrane potential
neuromuscular process controlling posture
detection of mechanical stimulus involved in sensory perception of pain
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)
NM_001165963
NM_001165964
NM_001202435
NM_006920
NM_001353948

NM_001353949
NM_001353950
NM_001353951
NM_001353952
NM_001353954
NM_001353955
NM_001353957
NM_001353958
NM_001353960
NM_001353961

NM_018733
NM_001313997

RefSeq (bjelančevina)
NP_001159435
NP_001159436
NP_001189364
NP_008851
NP_001340877

NP_001340878
NP_001340879
NP_001340880
NP_001340881
NP_001340883
NP_001340884
NP_001340886
NP_001340887
NP_001340889
NP_001340890

NP_001300926
NP_061203

Lokacija (UCSC)Chr 2: 165.98 – 166.15 MbChr 2: 66.1 – 66.27 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Lokacija gena

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Kodljudi, gen SCN1A nalazi se na hromosomu 2, i sastoji se od 26 egzona koji obuhvataju ukupnu dužinu od 6.030 parova nukleotidnih baza (bp).[9][10] Alternativna prerada egzona 5 dovodi do dva alternativna egzona.[11] Promotor je identificiran 2,5 kilobaznih parova (kb) uzvodno od mjesta početka transkripcije, a 5'-netranslirani egzoni mogu poboljšati ekspresiju gena SCN1A u SH-SY5Y ćelijama, ljudske ćelijske linije izvedenoj od neuroblastoma.[12]

Aminokiselinska sekvenca

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Dužina polipeptidnog lanca je 2.009 aminokiselina, a molekulska težina 228.972 Da.[5]

1020304050
MEQTVLVPPGPDSFNFFTRESLAAIERRIAEEKAKNPKPDKKDDDENGPK
PNSDLEAGKNLPFIYGDIPPEMVSEPLEDLDPYYINKKTFIVLNKGKAIF
RFSATSALYILTPFNPLRKIAIKILVHSLFSMLIMCTILTNCVFMTMSNP
PDWTKNVEYTFTGIYTFESLIKIIARGFCLEDFTFLRDPWNWLDFTVITF
AYVTEFVDLGNVSALRTFRVLRALKTISVIPGLKTIVGALIQSVKKLSDV
MILTVFCLSVFALIGLQLFMGNLRNKCIQWPPTNASLEEHSIEKNITVNY
NGTLINETVFEFDWKSYIQDSRYHYFLEGFLDALLCGNSSDAGQCPEGYM
CVKAGRNPNYGYTSFDTFSWAFLSLFRLMTQDFWENLYQLTLRAAGKTYM
IFFVLVIFLGSFYLINLILAVVAMAYEEQNQATLEEAEQKEAEFQQMIEQ
LKKQQEAAQQAATATASEHSREPSAAGRLSDSSSEASKLSSKSAKERRNR
RKKRKQKEQSGGEEKDEDEFQKSESEDSIRRKGFRFSIEGNRLTYEKRYS
SPHQSLLSIRGSLFSPRRNSRTSLFSFRGRAKDVGSENDFADDEHSTFED
NESRRDSLFVPRRHGERRNSNLSQTSRSSRMLAVFPANGKMHSTVDCNGV
VSLVGGPSVPTSPVGQLLPEVIIDKPATDDNGTTTETEMRKRRSSSFHVS
MDFLEDPSQRQRAMSIASILTNTVEELEESRQKCPPCWYKFSNIFLIWDC
SPYWLKVKHVVNLVVMDPFVDLAITICIVLNTLFMAMEHYPMTDHFNNVL
TVGNLVFTGIFTAEMFLKIIAMDPYYYFQEGWNIFDGFIVTLSLVELGLA
NVEGLSVLRSFRLLRVFKLAKSWPTLNMLIKIIGNSVGALGNLTLVLAII
VFIFAVVGMQLFGKSYKDCVCKIASDCQLPRWHMNDFFHSFLIVFRVLCG
EWIETMWDCMEVAGQAMCLTVFMMVMVIGNLVVLNLFLALLLSSFSADNL
AATDDDNEMNNLQIAVDRMHKGVAYVKRKIYEFIQQSFIRKQKILDEIKP
LDDLNNKKDSCMSNHTAEIGKDLDYLKDVNGTTSGIGTGSSVEKYIIDES
DYMSFINNPSLTVTVPIAVGESDFENLNTEDFSSESDLEESKEKLNESSS
SSEGSTVDIGAPVEEQPVVEPEETLEPEACFTEGCVQRFKCCQINVEEGR
GKQWWNLRRTCFRIVEHNWFETFIVFMILLSSGALAFEDIYIDQRKTIKT
MLEYADKVFTYIFILEMLLKWVAYGYQTYFTNAWCWLDFLIVDVSLVSLT
ANALGYSELGAIKSLRTLRALRPLRALSRFEGMRVVVNALLGAIPSIMNV
LLVCLIFWLIFSIMGVNLFAGKFYHCINTTTGDRFDIEDVNNHTDCLKLI
ERNETARWKNVKVNFDNVGFGYLSLLQVATFKGWMDIMYAAVDSRNVELQ
PKYEESLYMYLYFVIFIIFGSFFTLNLFIGVIIDNFNQQKKKFGGQDIFM
TEEQKKYYNAMKKLGSKKPQKPIPRPGNKFQGMVFDFVTRQVFDISIMIL
ICLNMVTMMVETDDQSEYVTTILSRINLVFIVLFTGECVLKLISLRHYYF
TIGWNIFDFVVVILSIVGMFLAELIEKYFVSPTLFRVIRLARIGRILRLI
KGAKGIRTLLFALMMSLPALFNIGLLLFLVMFIYAIFGMSNFAYVKREVG
IDDMFNFETFGNSMICLFQITTSAGWDGLLAPILNSKPPDCDPNKVNPGS
SVKGDCGNPSVGIFFFVSYIIISFLVVVNMYIAVILENFSVATEESAEPL
SEDDFEMFYEVWEKFDPDATQFMEFEKLSQFAAALEPPLNLPQPNKLQLI
AMDLPMVSGDRIHCLDILFAFTKRVLGESGEMDALRIQMEERFMASNPSK
VSYQPITTTLKRKQEEVSAVIIQRAYRRHLLKRTVKQASFTYNKNKIKGG
ANLLIKEDMIIDRINENSITEKTDLTMSTAACPPSYDRVTKPIVEKHEQE
GKDEKAKGK

Funkcija

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Kičmenjački natrijski kanal je naponski-ovisni ionki kanal, neophodan za stvaranje i širenje akcijskih potencijala, uglavnom u nervima i mišićima. Natrijski kanali osetljivi na napon su heteromerni kompleksi koji se sastoje od velike centralne glikozilovane alfa podjedinice koja stvara pore i dvije manje pomoćne beta podjedinice. Funkcionalne studije su pokazale da je transmembranska alfa podjedinica moždanih natrijevih kanala dovoljna za ekspresiju funkcionalnih natrijevih kanala.[13] Alfa podjedinice moždanih natrijskih kanala mozga formiraju potporodicu gena sa nekoliko strukturno različitih izoformi grupisanih na hromosomskoj ref+giji 2q24, tipovi I, II (Nav1.2) i III (Nav1.3). Također postoji nekoliko različitih izoformi alfa podjedinica natrijevih kanala u skeletnim i srčanim mišićima (Nav1.4[14] i Nav1.5).[15]

SCN1A gen kodira alfa podjedinicu napo-ovisnog natrijevog ionskog kanala, što ga čini članom deset paralognih porodica gena koje kodiraju naponski natrijev transmembranski protein NaV1.1. Unutar porodice gena koji kodiraju druge dijelove naponski-oviksnihnatrijskih kanala, mutacije SCN1A su prve identificirane, jer su mutacije ovog gena uzrokovale epilepsiju i febrilne napade.[16] Odista, gen SCN1A je jedan od najčešće mutiranih gena u ljudskom genomu koji je povezan s epilepsijom, što mu je dalo titulu „gena super krivca“.[17] Postoji 900 različitih mutacija prijavljenih za gen SCN1A, otprilike polovina prijavljenih mutacija su skraćivanja koja rezultiraju bez sinteze proteina.[18][19] Preostala polovina mutacija su misens mutacije, za koje se predviđa da će ili uzrokovati gubitsk funkcije ili dobitak funkcija, iako je vrlo malo njih testirano na funkcionalnost u laboratoriji.[9]

Suptilne razlike u naponskim kanalima natrijevih iona, mogu imati razorne fiziološke efekte i biti u osnovi abnormalnog neurološkog funkcionisanja.[20][21] 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).[18] Klinički, 70-80% pacijenata sa DS je identifikovano s mutacijama specifičnim za gen SCN1A, koje su uzrokovane de novo heterozigotnim mutacijama gena SCN1A.[22] Do sada postoje dvije baze podataka o SCN1A mutacijama, Infobase i SCN1A varijantna baza podataka Arhivirano 22. 7. 2019. na Wayback Machine.

Miševi s nok-in SCN1A mutacijama, koji su modelni organizmi za DS, brzo razvijaju napade, što ukazuje na značajno smanjenje funkcije NaV1.1.[10] Pretpostavljeno je da smanjene struje natrija zbog NaV1.1 mutacija mogu uzrokovati hipoekscitabilnost u GABA inhibitornim interneuronima, što dovodi do epilepsije.[12] Miševi i u homozigotnom i u heterozigotnolm stanju razvijaju fenotip napada i ataksiju. Iako homozigotni miševi umiru u prosjeku tokom druge do treće sedmice života, a otprilike 50% heterozigotnih nul-miševa preživi u odrasloj dobi.[10][12][23]

Klinički značaj

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Mutacije u genu SCN1A uzrokuju nasljedne febrilne napade i GEFS+, tip 2.[24][25][26][27]

Interakcije

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Pokazalo se da Nav1.1 ima reakcije sa sintropinom alfa 1.[28]

Također pogledajte

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Reference

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000144285 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000064329 - Ensembl, maj 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "Entrez Gene: SCN1A sodium channel, voltage-gated, type I, alpha subunit".
  6. ^ 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): 178–86. doi:10.1159/000133818. PMID 8062593.
  7. ^ Ito M, Nagafuji H, Okazawa H, Yamakawa K, Sugawara T, Mazaki-Miyazaki E, et al. (januar 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. PMID 11823106. S2CID 25555020.
  8. ^ Catterall WA, Goldin AL, Waxman SG (decembar 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. PMID 16382098. S2CID 7332624.
  9. ^ a b Meisler MH, O'Brien JE, Sharkey LM (juni 2010). "Sodium channel gene family: epilepsy mutations, gene interactions and modifier effects". The Journal of Physiology. 588 (Pt 11): 1841–8. doi:10.1113/jphysiol.2010.188482. PMC 2901972. PMID 20351042.
  10. ^ a b c Ogiwara I, Miyamoto H, Morita N, Atapour N, Mazaki E, Inoue I, et al. (maj 2007). "Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation". The Journal of Neuroscience. 27 (22): 5903–14. doi:10.1523/JNEUROSCI.5270-06.2007. PMC 6672241. PMID 17537961.
  11. ^ Tate SK, Depondt C, Sisodiya SM, Cavalleri GL, Schorge S, Soranzo N, et al. (april 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): 5507–12. Bibcode:2005PNAS..102.5507T. doi:10.1073/pnas.0407346102. PMC 556232. PMID 15805193.
  12. ^ a b c Long YS, Zhao QH, Su T, Cai YL, Zeng Y, Shi YW, et al. (novembar 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): 3375–81. doi:10.1002/jnr.21790. PMID 18655196. S2CID 33673297.
  13. ^ Goldin AL, Snutch T, Lübbert H, Dowsett A, Marshall J, Auld V, et al. (oktobar 1986). "Messenger RNA coding for only the alpha subunit of the rat brain Na channel is sufficient for expression of functional channels in Xenopus oocytes". Proceedings of the National Academy of Sciences of the United States of America. 83 (19): 7503–7. Bibcode:1986PNAS...83.7503G. doi:10.1073/pnas.83.19.7503. PMC 386747. PMID 2429308.
  14. ^ George AL, Komisarof J, Kallen RG, Barchi RL (februar 1992). "Primary structure of the adult human skeletal muscle voltage-dependent sodium channel". Annals of Neurology. 31 (2): 131–7. doi:10.1002/ana.410310203. PMID 1315496. S2CID 37892568.
  15. ^ Gellens ME, George AL, Chen LQ, Chahine M, Horn R, Barchi RL, Kallen RG (januar 1992). "Primary structure and functional expression of the human cardiac tetrodotoxin-insensitive voltage-dependent sodium channel". Proceedings of the National Academy of Sciences of the United States of America. 89 (2): 554–8. Bibcode:1992PNAS...89..554G. doi:10.1073/pnas.89.2.554. PMC 48277. PMID 1309946.
  16. ^ 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
  17. ^ 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
  18. ^ a b 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
  19. ^ 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
  20. ^ 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.
  21. ^ 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
  22. ^ 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.
  23. ^ 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
  24. ^ 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): 343–5. doi:10.1038/74159. PMID 10742094. S2CID 29543172.
  25. ^ Spampanato J, Escayg A, Meisler MH, Goldin AL (oktobar 2001). "Functional effects of two voltage-gated sodium channel mutations that cause generalized epilepsy with febrile seizures plus type 2". The Journal of Neuroscience. 21 (19): 7481–90. doi:10.1523/jneurosci.21-19-07481.2001. PMC 6762922. PMID 11567038.
  26. ^ Nabbout R, Gennaro E, Dalla Bernardina B, Dulac O, Madia F, Bertini E, et al. (juni 2003). "Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy". Neurology. 60 (12): 1961–7. doi:10.1212/01.wnl.0000069463.41870.2f. PMID 12821740. S2CID 604240.
  27. ^ Lossin C. "SCN1A infobase". Pristupljeno 30. 10. 2009. compilation of genetic variations in the SCN1A gene that alter the expression or function of Nav1.1
  28. ^ Gee SH, Madhavan R, Levinson SR, Caldwell JH, Sealock R, Froehner SC (januar 1998). "Interaction of muscle and brain sodium channels with multiple members of the syntrophin family of dystrophin-associated proteins". The Journal of Neuroscience. 18 (1): 128–37. doi:10.1523/jneurosci.18-01-00128.1998. PMC 6793384. PMID 9412493.

Dopunska literatura

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Vanjski linkovi

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Ovaj članak uključuje tekst iz Nacionalne medicinske biblioteke Sjedinjenih Država, koji je u javnom vlasništvu.