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Gene Review

SCN9A  -  sodium channel, voltage gated, type IX...

Homo sapiens

Synonyms: ETHA, FEB3B, GEFSP7, HSAN2D, NE-NA, ...
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Disease relevance of SCN9A

  • SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels [1].
  • Functional expression of voltage-gated sodium channel alpha-subunits (VGSCalphas), specifically Nav1.7, is associated with strong metastatic potential in prostate cancer (CaP) in vitro [2].
  • FINDINGS: Both subtypes of sodium channels PN1 and PN3 accumulated abnormally in human neuromas [3].

Psychiatry related information on SCN9A


High impact information on SCN9A

  • Other mutations in SCN9A associated with more negative activation thresholds are known to cause primary erythermalgia (PE) [4].
  • A genome-wide linkage search followed by mutational analysis of the candidate gene SCN9A, which encodes hNa(v)1.7, identified eight missense mutations in 11 families and 2 sporadic cases [4].
  • Action potentials were generated in cells expressing high levels of hNE-Na [6].
  • Transcripts were not identified in pituitary gland, brain, heart, liver or kidney, indicating that the hNE-Na is a sodium channel solely expressed in neuroendocrine cells [6].
  • The cDNA of hNE-Na (human neuroendocrine sodium channel) encodes a 1977 amino acid protein which phylogenetically represents a link between sodium channels isolated from skeletal muscle and brain [6].

Biological context of SCN9A


Anatomical context of SCN9A


Associations of SCN9A with chemical compounds

  • The PN1 channel was more susceptible to inhibition by mexiletine than PN3 [9].
  • Treatment of M-1 cells with 20 ng/ml TGF-beta1 significantly increased protein expression of PN-1 by 3.8+/-0.5-fold, whereas administration of 10(-6) M aldosterone markedly decreased protein expression of PN-1 to 53.7+/-6.7% [13].
  • Protease nexin-1 (PN-1), an inhibitor of serine proteases, contributes to tissue homeostasis and influences the behavior of some tumor cells [14].

Other interactions of SCN9A

  • We performed linkage analysis in a Chinese family with primary erythermalgia, and screened the mutations in the two candidate genes, SCN9A and GCA, in the family and a sporadic patient [15].
  • Remarkably, two voltage-gated sodium channel genes (Nav1.8 and Nav1.9) are expressed selectively in damage-sensing peripheral neurons, while a third channel (Nav1.7) is found predominantly in sensory and sympathetic neurons [16].
  • Stable expression and characterization of human PN1 and PN3 sodium channels [9].
  • Moreover, RT-PCR revealed the molecular evidence of high levels of mRNA for the functional ionic currents, including human MaxiK for I(KCa), Kv4.2 and Kv1.4 for I(to), heag1 for IK(DR), hNE-Na for I(Na.TTX), and CACNAIC for I(Ca.L) [17].

Analytical, diagnostic and therapeutic context of SCN9A


  1. SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels. Drenth, J.P., te Morsche, R.H., Guillet, G., Taieb, A., Kirby, R.L., Jansen, J.B. J. Invest. Dermatol. (2005) [Pubmed]
  2. A potential novel marker for human prostate cancer: voltage-gated sodium channel expression in vivo. Diss, J.K., Stewart, D., Pani, F., Foster, C.S., Walker, M.M., Patel, A., Djamgoz, M.B. Prostate Cancer Prostatic Dis. (2005) [Pubmed]
  3. Accumulation of PN1 and PN3 sodium channels in painful human neuroma-evidence from immunocytochemistry. Kretschmer, T., Happel, L.T., England, J.D., Nguyen, D.H., Tiel, R.L., Beuerman, R.W., Kline, D.G. Acta neurochirurgica. (2002) [Pubmed]
  4. SCN9A Mutations in Paroxysmal Extreme Pain Disorder: Allelic Variants Underlie Distinct Channel Defects and Phenotypes. Fertleman, C.R., Baker, M.D., Parker, K.A., Moffatt, S., Elmslie, F.V., Abrahamsen, B., Ostman, J., Klugbauer, N., Wood, J.N., Gardiner, R.M., Rees, M. Neuron (2006) [Pubmed]
  5. Mechanism of thrombin clearance by human astrocytoma cells. Mentz, S., de Lacalle, S., Baerga-Ortiz, A., Knauer, M.F., Knauer, D.J., Komives, E.A. J. Neurochem. (1999) [Pubmed]
  6. Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells. Klugbauer, N., Lacinova, L., Flockerzi, V., Hofmann, F. EMBO J. (1995) [Pubmed]
  7. Expression of alternatively spliced sodium channel alpha-subunit genes. Unique splicing patterns are observed in dorsal root ganglia. Raymond, C.K., Castle, J., Garrett-Engele, P., Armour, C.D., Kan, Z., Tsinoremas, N., Johnson, J.M. J. Biol. Chem. (2004) [Pubmed]
  8. Genetic heterogeneity and exclusion of a modifying locus at 2q in a family with autosomal dominant primary erythermalgia. Burns, T.M., Te Morsche, R.H., Jansen, J.B., Drenth, J.P. Br. J. Dermatol. (2005) [Pubmed]
  9. Stable expression and characterization of human PN1 and PN3 sodium channels. Akiba, I., Seki, T., Mori, M., Iizuka, M., Nishimura, S., Sasaki, S., Imoto, K., Barsoumian, E.L. Recept. Channels (2003) [Pubmed]
  10. Voltage-gated sodium channel expressed in cultured human smooth muscle cells: involvement of SCN9A. Jo, T., Nagata, T., Iida, H., Imuta, H., Iwasawa, K., Ma, J., Hara, K., Omata, M., Nagai, R., Takizawa, H., Nagase, T., Nakajima, T. FEBS Lett. (2004) [Pubmed]
  11. Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons. Dib-Hajj, S.D., Rush, A.M., Cummins, T.R., Hisama, F.M., Novella, S., Tyrrell, L., Marshall, L., Waxman, S.G. Brain (2005) [Pubmed]
  12. Potent modulation of the voltage-gated sodium channel Nav1.7 by OD1, a toxin from the scorpion Odonthobuthus doriae. Maertens, C., Cuypers, E., Amininasab, M., Jalali, A., Vatanpour, H., Tytgat, J. Mol. Pharmacol. (2006) [Pubmed]
  13. Inhibition of prostasin-induced ENaC activities by PN-1 and regulation of PN-1 expression by TGF-beta1 and aldosterone. Wakida, N., Kitamura, K., Tuyen, D.G., Maekawa, A., Miyoshi, T., Adachi, M., Shiraishi, N., Ko, T., Ha, V., Nonoguchi, H., Tomita, K. Kidney Int. (2006) [Pubmed]
  14. Activation of ERK signaling upon alternative protease nexin-1 internalization mediated by syndecan-1. Li, X., Herz, J., Monard, D. J. Cell. Biochem. (2006) [Pubmed]
  15. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. Yang, Y., Wang, Y., Li, S., Xu, Z., Li, H., Ma, L., Fan, J., Bu, D., Liu, B., Fan, Z., Wu, G., Jin, J., Ding, B., Zhu, X., Shen, Y. J. Med. Genet. (2004) [Pubmed]
  16. Voltage-gated sodium channels and pain pathways. Wood, J.N., Boorman, J.P., Okuse, K., Baker, M.D. J. Neurobiol. (2004) [Pubmed]
  17. Characterization of ionic currents in human mesenchymal stem cells from bone marrow. Li, G.R., Sun, H., Deng, X., Lau, C.P. Stem Cells (2005) [Pubmed]
  18. Painful channels. Catterall, W.A., Yu, F.H. Neuron (2006) [Pubmed]
  19. An SCN9A channelopathy causes congenital inability to experience pain. Cox, J.J., Reimann, F., Nicholas, A.K., Thornton, G., Roberts, E., Springell, K., Karbani, G., Jafri, H., Mannan, J., Raashid, Y., Al-Gazali, L., Hamamy, H., Valente, E.M., Gorman, S., Williams, R., McHale, D.P., Wood, J.N., Gribble, F.M., Woods, C.G. Nature (2006) [Pubmed]
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