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Gene Review

SCN2A  -  sodium channel, voltage gated, type II...

Homo sapiens

Synonyms: BFIC3, BFIS3, BFNIS, EIEE11, HBA, ...
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Disease relevance of SCN2A

  • Mutations in two of these genes, SCN1A and SCN2A, result in the seizure disorder GEFS+ [1].
  • Even though a small pedigree could not show clear cosegregation with the disease phenotype, these findings strongly suggest the involvement of Na(v)1.2 in a human disease and propose the R188W [corrected] mutation as the genetic defect responsible for febrile seizures associated with afebrile seizures [2].
  • Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger [3].
  • Tested on recombinant rat Na(v)1.2 channels and native Na(+) currents in cultured rat dorsal root ganglion neurons, PPPA was approximately 1000 times more potent, had 2000-fold faster binding kinetics, and > or =10-fold higher levels of state dependence than CBZ and LTG [4].
  • The recently developed monoclonal antibody HBA 71 is specific for the product MIC2, a marker of peripheral primitive neuroectodermal tumors [5].

Psychiatry related information on SCN2A

  • These results suggest that the EDAC screen may provide an efficient alternative screening tool for the identification of heavy alcohol consumption not HBA as it identifies applicants with both normal or abnormal liver enzymes and HDL-C [6].

High impact information on SCN2A

  • A missense mutation of the Na+ channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction [2].
  • Thus, the C terminus has a strong influence on kinetics and voltage dependence of inactivation in brain Na(v)1.2 and cardiac Na(v)1.5 channels and is primarily responsible for their differing rates of channel inactivation [7].
  • Hybridization of DNA fragments from the 3' untranslated region of HBA and PCR with primers derived from HBB with human-hamster somatic cell hybrids localized these clones to human chromosome 2 [8].
  • 3. The sodium channel HBA gene product was expressed by transfection in CHO cells [8].
  • Ligation of three overlapping clones generated a full-length cDNA clone, HBA, that provided the complete nucleotide sequence coding for a protein of 2005 amino acids [8].

Biological context of SCN2A

  • The variant R1902C in SCN2A is located in the calmodulin binding site and was found to reduce binding affinity for calcium-bound calmodulin [1].
  • Although no DFNA16-causing mutations were found in either gene, haplotype analysis with polymorphic markers in SCN2A introns further narrowed the candidate gene interval to the region flanked by D2S354 and STS SHGC-82894 [9].
  • In situ hybridization to human metaphase chromosomes mapped the structural genes for both HBA and HBB sodium channels to chromosome 2q23-24 [8].
  • Also, the intensive luminescence of the Eu(III) ions by the photoexcitation of the ligand in NAC-1 and NAC-2 in polar solvents supports that the energy transfer from the ligand to the Eu(III) ion takes place efficiently [10].
  • A DNA probe derived from a human genomic library has been used to localize on human chromosomes a gene coding for the alpha-subunit of the brain type II sodium channel (SCN2A) [11].

Anatomical context of SCN2A

  • After showing that SCN2A is expressed in human fetal cochlea, we determined its genomic structure to facilitate mutation screening in our DFNA16 kindred [9].
  • In Xenopus oocytes, Nedd4-2 strongly inhibited the activities of all three Na(v)s (Na(v)1.2, Na(v)1.7, and Na(v)1.8) tested [12].
  • We further showed that the carboxyl termini fusion proteins of one central nervous system and one peripheral nervous system-derived Na(+) channel (Na(v)1.2 and Na(v)1.7, respectively) are readily ubiquitinated by Nedd4-2 [12].
  • During development, Na(v)1.2 channels first associate with ankyrin-G in the inner plexiform layer but are later replaced by Na(v)1.1, similar to the switch from Na(v)1.2 to Na(v)1.6 at nodes of Ranvier and initial segments [13].
  • The effects of the legal drug nicotine, now known to be the addictive substance of cigarette smoke, was discussed in regards to effects on both the neurologic and immunologic system in rodents in terms of antibody formation and T cell function, related to HBA activation and proinflammatory cytokine responses [14].

Associations of SCN2A with chemical compounds

  • In contrast, beta2 caused a sialic acid-independent depolarizing shift in Nav1.2 gating [15].
  • On the basis of published mutagenesis studies and the present SARs, we speculate that the S(1) HBA/D group might be identified as the hydroxyl of alpha(1)-Tyr209 or of other neighboring amino acids [16].
  • In the present study, we identified a second population of mRNA suspected to encode a new brain adenylyl cyclase (HBA C2) [17].
  • The probe corresponding to HBA C1 exhibited a strong specific signal on chromosome 8q24, with a major peak in the band q24 [17].
  • The perfluorinated heptanol [CF(3)(CF(2))(5)CH(2)OH], which produces anesthesia, inhibited the Na(v)1.2 channel like other alcohols tested (ethanol, heptanol, and CF(3)CH(2)OH), even though this compound does not affect GABA, glycine, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, or kainate receptors [18].

Regulatory relationships of SCN2A

  • When expressed in HEK-293 cells and studied using whole cell voltage clamping, the neuronal Na(v)1.2 and Na(v)1.3 were also downregulated by Nedd4-2 [19].

Other interactions of SCN2A

  • Haploinsufficiency of Na(v)1.2 protein is one plausible explanation for the pathology of this patient; however, our biophysical findings suggest that the R102X truncated protein exerts a dominant negative effect leading to the patient's intractable epilepsy [20].
  • 2. In Nav1.2 or Nav1.5, CaM bound to a localized region containing the IQ motif and did not support the large Ca(2+)-dependent conformational change seen in the Cav1.2.CaM complex [21].
  • When sialylation was reduced, only the sialic acid-independent depolarizing effects of beta2 on Nav1.2 gating were apparent [15].
  • In vivo, BAF57 occupies the neuronal sodium channel gene (Nav1.2) promoter, and targeting to this gene requires REST [22].
  • Pull-down experiments using fusion proteins bearing the PY motif of Na(v)1.2, Na(v)1.3, and Na(v)1.5 indicated that mouse brain Nedd4-2 binds to the Na(v) PY motif [19].

Analytical, diagnostic and therapeutic context of SCN2A

  • The regional localisation of the alpha globin (HBA) complex on the short arm of chromosome 16 was investigated by in situ hybridisation, Southern blot analysis, and linkage analysis using the fragile site at 16p12.3 (FRA16A) and translocation breakpoints within band 16p13 [23].
  • By analyzing the expression of mRNAs encoding TTX-sensitive Na(+) channel alpha subunits with standard RT-PCR and specific primers, we detected Na(v)1.2, Na(v)1.4, Na(v)1.6, and Na(v)1.7 transcripts in total RNA obtained from primary cultures and biopsies of CaC [24].
  • Both irradiated samples of HBA and HBS were denatured, digested with trypsin, and then separated by reversed-phase HPLC [25].
  • HBA 71 and anti-beta 2-microglobulin, when used in combination, can facilitate the differential diagnosis of PN and NBL [5].
  • Finally, perfusion with HBA containing 10 mumol/l AA plus 10 mumol/l EPA resulted in a significant greater production of PGI2-like material than perfusion with HBA-AA alone [26].


  1. Sodium channels SCN1A, SCN2A and SCN3A in familial autism. Weiss, L.A., Escayg, A., Kearney, J.A., Trudeau, M., MacDonald, B.T., Mori, M., Reichert, J., Buxbaum, J.D., Meisler, M.H. Mol. Psychiatry (2003) [Pubmed]
  2. A missense mutation of the Na+ channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction. Sugawara, T., Tsurubuchi, Y., Agarwala, K.L., Ito, M., Fukuma, G., Mazaki-Miyazaki, E., Nagafuji, H., Noda, M., Imoto, K., Wada, K., Mitsudome, A., Kaneko, S., Montal, M., Nagata, K., Hirose, S., Yamakawa, K. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  3. Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger. Craner, M.J., Newcombe, J., Black, J.A., Hartle, C., Cuzner, M.L., Waxman, S.G. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  4. Pharmacology of 2-[4-(4-chloro-2-fluorophenoxy)phenyl]-pyrimidine-4-carboxamide: a potent, broad-spectrum state-dependent sodium channel blocker for treating pain states. Ilyin, V.I., Pomonis, J.D., Whiteside, G.T., Harrison, J.E., Pearson, M.S., Mark, L., Turchin, P.I., Gottshall, S., Carter, R.B., Nguyen, P., Hogenkamp, D.J., Olanrewaju, S., Benjamin, E., Woodward, R.M. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  5. Use of HBA 71 and anti-beta 2-microglobulin to distinguish peripheral neuroepithelioma from neuroblastoma. Pappo, A.S., Douglass, E.C., Meyer, W.H., Marina, N., Parham, D.M. Hum. Pathol. (1993) [Pubmed]
  6. A new century approach for alcohol screen in the insurance industry. Bean, P., Kleaver, E., Roberts, B., Harasymiw, J. Journal of insurance medicine (New York, N.Y.) (2001) [Pubmed]
  7. Role of the C-terminal domain in inactivation of brain and cardiac sodium channels. Mantegazza, M., Yu, F.H., Catterall, W.A., Scheuer, T. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  8. Primary structure, chromosomal localization, and functional expression of a voltage-gated sodium channel from human brain. Ahmed, C.M., Ware, D.H., Lee, S.C., Patten, C.D., Ferrer-Montiel, A.V., Schinder, A.F., McPherson, J.D., Wagner-McPherson, C.B., Wasmuth, J.J., Evans, G.A. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  9. Genomic structures of SCN2A and SCN3A - candidate genes for deafness at the DFNA16 locus. Kasai, N., Fukushima, K., Ueki, Y., Prasad, S., Nosakowski, J., Sugata, K., Sugata, A., Nishizaki, K., Meyer, N.C., Smith, R.J. Gene (2001) [Pubmed]
  10. Sensitized emission of luminescent lanthanide complexes based on 4-naphthalen-1-yl-benzoic acid derivatives by a charge-transfer process. Kim, Y.H., Baek, N.S., Kim, H.K. Chemphyschem : a European journal of chemical physics and physical chemistry. (2006) [Pubmed]
  11. Localization of a human brain sodium channel gene (SCN2A) to chromosome 2. Litt, M., Luty, J., Kwak, M., Allen, L., Magenis, R.E., Mandel, G. Genomics (1989) [Pubmed]
  12. Regulation of neuronal voltage-gated sodium channels by the ubiquitin-protein ligases Nedd4 and Nedd4-2. Fotia, A.B., Ekberg, J., Adams, D.J., Cook, D.I., Poronnik, P., Kumar, S. J. Biol. Chem. (2004) [Pubmed]
  13. Novel clustering of sodium channel Na(v)1.1 with ankyrin-G and neurofascin at discrete sites in the inner plexiform layer of the retina. Van Wart, A., Boiko, T., Trimmer, J.S., Matthews, G. Mol. Cell. Neurosci. (2005) [Pubmed]
  14. Neurological basis of drug dependence and its effects on the immune system. Friedman, H., Eisenstein, T.K. J. Neuroimmunol. (2004) [Pubmed]
  15. Isoform-specific effects of the beta2 subunit on voltage-gated sodium channel gating. Johnson, D., Bennett, E.S. J. Biol. Chem. (2006) [Pubmed]
  16. Refinement of the benzodiazepine receptor site topology by structure-activity relationships of new N-(heteroarylmethyl)indol-3-ylglyoxylamides. Primofiore, G., Da Settimo, F., Marini, A.M., Taliani, S., La Motta, C., Simorini, F., Novellino, E., Greco, G., Cosimelli, B., Ehlardo, M., Sala, A., Besnard, F., Montali, M., Martini, C. J. Med. Chem. (2006) [Pubmed]
  17. Different chromosomal localization of two adenylyl cyclase genes expressed in human brain. Stengel, D., Parma, J., Gannagé, M.H., Roeckel, N., Mattei, M.G., Barouki, R., Hanoune, J. Hum. Genet. (1992) [Pubmed]
  18. Effects of alcohols and anesthetics on recombinant voltage-gated Na+ channels. Shiraishi, M., Harris, R.A. J. Pharmacol. Exp. Ther. (2004) [Pubmed]
  19. Molecular determinants of voltage-gated sodium channel regulation by the Nedd4/Nedd4-like proteins. Rougier, J.S., van Bemmelen, M.X., Bruce, M.C., Jespersen, T., Gavillet, B., Apothéloz, F., Cordonier, S., Staub, O., Rotin, D., Abriel, H. Am. J. Physiol., Cell Physiol. (2005) [Pubmed]
  20. A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline. Kamiya, K., Kaneda, M., Sugawara, T., Mazaki, E., Okamura, N., Montal, M., Makita, N., Tanaka, M., Fukushima, K., Fujiwara, T., Inoue, Y., Yamakawa, K. J. Neurosci. (2004) [Pubmed]
  21. Calmodulin mediates Ca2+ sensitivity of sodium channels. Kim, J., Ghosh, S., Liu, H., Tateyama, M., Kass, R.S., Pitt, G.S. J. Biol. Chem. (2004) [Pubmed]
  22. REST repression of neuronal genes requires components of the hSWI.SNF complex. Battaglioli, E., Andrés, M.E., Rose, D.W., Chenoweth, J.G., Rosenfeld, M.G., Anderson, M.E., Mandel, G. J. Biol. Chem. (2002) [Pubmed]
  23. Mapping the human alpha globin gene complex to 16p13.2----pter. Simmers, R.N., Mulley, J.C., Hyland, V.J., Callen, D.F., Sutherland, G.R. J. Med. Genet. (1987) [Pubmed]
  24. Functional expression of voltage-gated sodium channels in primary cultures of human cervical cancer. Diaz, D., Delgadillo, D.M., Hern??ndez-Gallegos, E., Ram??rez-Dom??nguez, M.E., Hinojosa, L.M., Ortiz, C.S., Berumen, J., Camacho, J., Gomora, J.C. J. Cell. Physiol. (2007) [Pubmed]
  25. Photoaffinity labelling of cyanomethaemoglobin with derivatives of tryptophan and 5-bromotryptophan. Li, M., Lin, Z., Johnson, M.E. Biochem. J. (1995) [Pubmed]
  26. Eicosapentaenoic acid potentiates the production of prostacyclin-like material in the arachidonic acid perfused human umbilical vein. Kristensen, S.D., Arnfred, T., Dyerberg, J. Thromb. Res. (1984) [Pubmed]
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