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Gene Review

SCN4A  -  sodium channel, voltage gated, type IV...

Homo sapiens

Synonyms: HOKPP2, HYKPP, HYPP, NAC1A, Na(V)1.4, ...
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Disease relevance of SCN4A


High impact information on SCN4A


Chemical compound and disease context of SCN4A


Biological context of SCN4A

  • However, MH has been shown to be genetically heterogeneous, and in the ensuing search for other MHS genes, a locus on chromosome 17q has been proposed, and the gene for the adult muscle sodium channel (SCN4A) was suggested as a candidate [15].
  • One family harbored a new heterozygous point mutation C2014A in exon 12 (R672S) of SCN4A [16].
  • Restriction mapping and hybridization analysis of YAC and cosmid clones confirmed the close linkage of the CD79b gene to the hGH gene cluster and facilitated the assembly of a 100-kb physical map linking the hGH locus, the CD79b gene, and the more distant muscle-specific sodium channel alpha-subunit (SCN4A) gene [17].
  • Reported herein are two Korean hypokalemic periodic paralysis families, one carrying a novel SCN4A Arg672Cys mutation with incomplete penetrance in women, and the other carrying a CACNL1A3 Arg528His mutation, with the onset of characteristics of hypoPP developing at an earlier age, as well as a higher penetrance rate in women [2].
  • In the human and rat genomes, the B29 gene is located between the skeletal muscle-specific Na-channel alpha subunit (SCN4A) gene and the pituitary-specific growth hormone (GH-N) gene [18].

Anatomical context of SCN4A

  • The authors screened the skeletal muscle sodium channel gene (SCN4A) in the remainder [16].
  • In contrast to other disease-causing mutations in SCN1A, SCN1B and SCN4A, the only mechanism that could explain hyperexcitability of the cell membrane would be the acceleration of activation [1].
  • Interestingly, intron 21 of the same SCN4A gene and the corresponding intron 25 of the SCN5A cardiac muscle sodium channel gene also have 5'-AT and AC-3' boundaries, but they have divergent 5' splice site and presumptive branch site sequences [19].
  • Specific hSkM1 RNA transcripts are expressed in adult human skeletal muscle but not in heart, brain, or uterus [20].
  • We used the macropatch technique on Xenopus oocytes to study hSkM1 and hH1 slow inactivation with and without beta(1)-subunit coexpression [21].

Associations of SCN4A with chemical compounds

  • A novel SCN4A mutation causing the replacement of Val445 in the sixth transmembrane segment of domain 1 with methionine was discovered in all affected individuals and is the likely genetic basis for the syndrome [5].
  • Some remarkable clinical features were observed in a large hypoPP family carrying an SCN4A mutation: a complete penetrance in men and women, an early age at onset, postcritic myalgias and an increased number and severity of attacks induced by acetazolamide [22].
  • CONCLUSIONS: The current report provides direct evidence that succinylcholine-induced MMR, whole-body rigidity, and an abnormal IVCT result are associated with a mutation in the SCN4A gene [12].
  • Salbutamol treatment in a patient with hyperkalaemic periodic paralysis due to a mutation in the skeletal muscle sodium channel gene (SCN4A) [23].
  • All affected family members carried the threonine to methionine substitution at codon 704 (T704M) in exon 13 of the skeletal muscle voltage gated sodium channel gene (SCN4A) [24].

Regulatory relationships of SCN4A

  • When selectively applied to channels after inducing slow inactivation with a 60-s pulse to -10 mV, mibefradil (1 microM) produced 45% fractional block in Nav1.5 and greater block (88%) in an isoform (Nav1.4) that slow-inactivates more completely [25].

Other interactions of SCN4A

  • Our results exclude the alpha 1, beta 1, and gamma subunit of the DHP receptor as well as the SCN4A locus as candidates for the molecular defect in MHS for these pedigrees where also the RYR1 on chromosome 19q13.1 has been excluded [15].
  • We now studied the second GEFS+ mutation (T875M in SCN1A), using the highly homologous SCN4A gene (mutation T685M) [1].
  • The authors conclude that SCN4A mutations are an uncommon cause of hypoPP in this UK population [16].
  • Our results exclude the alpha 1, beta 1 and gamma subunit of the DHP receptor as well as the SCN4A locus from that region [15].
  • Linkage to two loci implicated in other myotonic disorders, the muscle chloride channel (CLCN1) gene, and the muscle sodium channel (SCN4A) gene, was assessed and excluded [26].

Analytical, diagnostic and therapeutic context of SCN4A


  1. Enhanced inactivation and acceleration of activation of the sodium channel associated with epilepsy in man. Alekov, A.K., Rahman, M.M., Mitrovic, N., Lehmann-Horn, F., Lerche, H. Eur. J. Neurosci. (2001) [Pubmed]
  2. Mutation screening in Korean hypokalemic periodic paralysis patients: a novel SCN4A Arg672Cys mutation. Kim, M.K., Lee, S.H., Park, M.S., Kim, B.C., Cho, K.H., Lee, M.C., Kim, J.H., Kim, S.M. Neuromuscul. Disord. (2004) [Pubmed]
  3. Novel mutations in families with unusual and variable disorders of the skeletal muscle sodium channel. McClatchey, A.I., McKenna-Yasek, D., Cros, D., Worthen, H.G., Kuncl, R.W., DeSilva, S.M., Cornblath, D.R., Gusella, J.F., Brown, R.H. Nat. Genet. (1992) [Pubmed]
  4. Identification of a mutation in the gene causing hyperkalemic periodic paralysis. Ptácek, L.J., George, A.L., Griggs, R.C., Tawil, R., Kallen, R.G., Barchi, R.L., Robertson, M., Leppert, M.F. Cell (1991) [Pubmed]
  5. A novel muscle sodium channel mutation causes painful congenital myotonia. Rosenfeld, J., Sloan-Brown, K., George, A.L. Ann. Neurol. (1997) [Pubmed]
  6. Temperature-sensitive mutations in the III-IV cytoplasmic loop region of the skeletal muscle sodium channel gene in paramyotonia congenita. McClatchey, A.I., Van den Bergh, P., Pericak-Vance, M.A., Raskind, W., Verellen, C., McKenna-Yasek, D., Rao, K., Haines, J.L., Bird, T., Brown, R.H. Cell (1992) [Pubmed]
  7. U1-mediated exon definition interactions between AT-AC and GT-AG introns. Wu, Q., Krainer, A.R. Science (1996) [Pubmed]
  8. Myasthenic syndrome caused by mutation of the SCN4A sodium channel. Tsujino, A., Maertens, C., Ohno, K., Shen, X.M., Fukuda, T., Harper, C.M., Cannon, S.C., Engel, A.G. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  9. Dinucleotide repeat polymorphisms at the SCN4A locus suggest allelic heterogeneity of hyperkalemic periodic paralysis and paramyotonia congenita. McClatchey, A.I., Trofatter, J., McKenna-Yasek, D., Raskind, W., Bird, T., Pericak-Vance, M., Gilchrist, J., Arahata, K., Radosavljevic, D., Worthen, H.G. Am. J. Hum. Genet. (1992) [Pubmed]
  10. Functional consequences of a domain 1/S6 segment sodium channel mutation associated with painful congenital myotonia. Wang, D.W., VanDeCarr, D., Ruben, P.C., George, A.L., Bennett, P.B. FEBS Lett. (1999) [Pubmed]
  11. A new mutation in a family with cold-aggravated myotonia disrupts Na(+) channel inactivation. Wu, F.F., Takahashi, M.P., Pegoraro, E., Angelini, C., Colleselli, P., Cannon, S.C., Hoffman, E.P. Neurology (2001) [Pubmed]
  12. Masseter muscle rigidity associated with glycine1306-to-alanine mutation in the adult muscle sodium channel alpha-subunit gene. Vita, G.M., Olckers, A., Jedlicka, A.E., George, A.L., Heiman-Patterson, T., Rosenberg, H., Fletcher, J.E., Levitt, R.C. Anesthesiology (1995) [Pubmed]
  13. SCN4A-associated hypokalemic periodic paralysis merits a trial of acetazolamide. Venance, S.L., Jurkat-Rott, K., Lehmann-Horn, F., Tawil, R. Neurology (2004) [Pubmed]
  14. The human skeletal muscle Na channel mutation R669H associated with hypokalemic periodic paralysis enhances slow inactivation. Struyk, A.F., Scoggan, K.A., Bulman, D.E., Cannon, S.C. J. Neurosci. (2000) [Pubmed]
  15. Exclusion of malignant hyperthermia susceptibility (MHS) from a putative MHS2 locus on chromosome 17q and of the alpha 1, beta 1, and gamma subunits of the dihydropyridine receptor calcium channel as candidates for the molecular defect. Sudbrak, R., Golla, A., Hogan, K., Powers, P., Gregg, R., Du Chesne, I., Lehmann-Horn, F., Deufel, T. Hum. Mol. Genet. (1993) [Pubmed]
  16. Sodium channel gene mutations in hypokalemic periodic paralysis: an uncommon cause in the UK. Davies, N.P., Eunson, L.H., Samuel, M., Hanna, M.G. Neurology (2001) [Pubmed]
  17. Physical linkage of the human growth hormone gene cluster and the CD79b (Ig beta/B29) gene. Bennani-Baïti, I.M., Cooke, N.E., Liebhaber, S.A. Genomics (1998) [Pubmed]
  18. A conserved sequence upstream of the B29 (Ig beta, CD79b) gene interacts with YY1. Patrone, L., Henson, S.E., Wall, R., Malone, C.S. Mol. Biol. Rep. (2004) [Pubmed]
  19. Splicing of a divergent subclass of AT-AC introns requires the major spliceosomal snRNAs. Wu, Q., Krainer, A.R. RNA (1997) [Pubmed]
  20. Primary structure of the adult human skeletal muscle voltage-dependent sodium channel. George, A.L., Komisarof, J., Kallen, R.G., Barchi, R.L. Ann. Neurol. (1992) [Pubmed]
  21. Structural determinants of slow inactivation in human cardiac and skeletal muscle sodium channels. Vilin, Y.Y., Makita, N., George, A.L., Ruben, P.C. Biophys. J. (1999) [Pubmed]
  22. Hypokalaemic periodic paralysis type 2 caused by mutations at codon 672 in the muscle sodium channel gene SCN4A. Sternberg, D., Maisonobe, T., Jurkat-Rott, K., Nicole, S., Launay, E., Chauveau, D., Tabti, N., Lehmann-Horn, F., Hainque, B., Fontaine, B. Brain (2001) [Pubmed]
  23. Salbutamol treatment in a patient with hyperkalaemic periodic paralysis due to a mutation in the skeletal muscle sodium channel gene (SCN4A). Hanna, M.G., Stewart, J., Schapira, A.H., Wood, N.W., Morgan-Hughes, J.A., Murray, N.M. J. Neurol. Neurosurg. Psychiatr. (1998) [Pubmed]
  24. Severe infantile hyperkalaemic periodic paralysis and paramyotonia congenita: broadening the clinical spectrum associated with the T704M mutation in SCN4A. Brancati, F., Valente, E.M., Davies, N.P., Sarkozy, A., Sweeney, M.G., LoMonaco, M., Pizzuti, A., Hanna, M.G., Dallapiccola, B. J. Neurol. Neurosurg. Psychiatr. (2003) [Pubmed]
  25. State-dependent mibefradil block of Na+ channels. McNulty, M.M., Hanck, D.A. Mol. Pharmacol. (2004) [Pubmed]
  26. Proximal myotonic dystrophy--a family with autosomal dominant muscular dystrophy, cataracts, hearing loss and hypogonadism: heterogeneity of proximal myotonic syndromes? Udd, B., Krahe, R., Wallgren-Pettersson, C., Falck, B., Kalimo, H. Neuromuscul. Disord. (1997) [Pubmed]
  27. A mutation in the KCNE3 potassium channel gene is associated with susceptibility to thyrotoxic hypokalemic periodic paralysis. Dias Da Silva, M.R., Cerutti, J.M., Arnaldi, L.A., Maciel, R.M. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  28. Clinical, electrophysiological, and molecular genetic studies in a new family with paramyotonia congenita. Davies, N.P., Eunson, L.H., Gregory, R.P., Mills, K.R., Morrison, P.J., Hanna, M.G. J. Neurol. Neurosurg. Psychiatr. (2000) [Pubmed]
  29. Altered gene expression in steroid-treated denervated muscle. Rich, M.M., Kraner, S.D., Barchi, R.L. Neurobiol. Dis. (1999) [Pubmed]
  30. Dysregulation of sodium channel gating in critical illness myopathy. Teener, J.W., Rich, M.M. J. Muscle Res. Cell. Motil. (2006) [Pubmed]
  31. A phenylalanine residue at segment D3-S6 in Nav1.4 voltage-gated Na(+) channels is critical for pyrethroid action. Wang, S.Y., Barile, M., Wang, G.K. Mol. Pharmacol. (2001) [Pubmed]
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