Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. It is expressed in skeletal muscle, and mutations in this gene have been linked to several myotonia and periodic paralysis disorders.
In hypokalemic periodic paralysis, arginine residues making up the voltage sensor of Nav1.4 are mutated. The voltage sensor comprises the S4 alpha helix of each of the four transmembrane domains (I-IV) of the protein, and contains basic residues that only allow entry of the positive sodium ions at appropriate membrane voltages by blocking or opening the channel pore. In patients with these mutations, the channel has a reduced excitability and signals from the central nervous system are unable to depolarise muscle. As a result, the muscle cannot contract efficiently, causing paralysis. The condition is hypokalemic because a low extracellular potassium ion concentration will cause the muscle to repolarise to the resting potential more quickly, so even if calcium conductance does occur it cannot be sustained. It becomes more difficult to reach the calcium threshold at which the muscle can contract, and even if this is reached then the muscle is more likely to relax. Because of this, the severity would be reduced if potassium ion concentrations are kept high.
In hyperkalemic periodic paralysis, mutations occur in residues between transmembrane domains III and IV which make up the fast inactivation gate of Nav1.4. Mutations have also been found on the cytoplasmic loops between the S4 and S5 helices of domains II, III and IV, which are the binding sites of the inactivation gate.
In patients with these the channel is unable to inactivate, sodium conductance is sustained and the muscle remains permanently tense. Since the motor end plate is depolarized, further signals to contract have no effect (paralysis). The condition is hyperkalemic because a high extracellular potassium ion concentration will make it even more unfavourable for potassium to leave the cell in order to repolarise it to the resting potential, and this further prolongs the sodium conductance and keeps the muscle contracted. Hence, the severity would be reduced if extracellular (serum) potassium ion concentrations are kept low.
The same types of mutations cause myotonia and paralysis, however the difference between these phenotypes depends on the level of sodium current that persists. If the conductance fluctuates below the voltage threshold for Nav1.4, then the sodium channels will eventually be able to close, and be depolarised again. Thus, the muscle merely remains contracted for longer than normal (myotonia) but will relax and be able to contract again within a short period. If the conductance settles at a steady state with the sodium pore open and unable to inactivate, then the muscle is unable to relax at all and motor control is completely lost (paralysis).
^Ptacek LJ, George AL Jr, Griggs RC, Tawil R, Kallen RG, Barchi RL, Robertson M, Leppert MF (Jan 1992). "Identification of a mutation in the gene causing hyperkalemic periodic paralysis". Cell67 (5): 1021–7. doi:10.1016/0092-8674(91)90374-8. PMID1659948.
^Catterall WA, Goldin AL, Waxman SG (Dec 2005). "International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels". Pharmacol Rev57 (4): 397–409. doi:10.1124/pr.57.4.4. PMID16382098.
Wang JZ, Rojas CV, Zhou JH, et al. (1992). "Sequence and genomic structure of the human adult skeletal muscle sodium channel alpha subunit gene on 17q". Biochem. Biophys. Res. Commun.182 (2): 794–801. doi:10.1016/0006-291X(92)91802-W. PMID1310396.
Ptacek LJ, Tawil R, Griggs RC, et al. (1992). "Linkage of atypical myotonia congenita to a sodium channel locus". Neurology42 (2): 431–3. doi:10.1212/wnl.42.2.431. PMID1310531.
McClatchey AI, Van den Bergh P, Pericak-Vance MA, et al. (1992). "Temperature-sensitive mutations in the III-IV cytoplasmic loop region of the skeletal muscle sodium channel gene in paramyotonia congenita". Cell68 (4): 769–74. doi:10.1016/0092-8674(92)90151-2. PMID1310898.
George AL, Komisarof J, Kallen RG, Barchi RL (1992). "Primary structure of the adult human skeletal muscle voltage-dependent sodium channel". Ann. Neurol.31 (2): 131–7. doi:10.1002/ana.410310203. PMID1315496.
Ptácek LJ, George AL, Barchi RL, et al. (1992). "Mutations in an S4 segment of the adult skeletal muscle sodium channel cause paramyotonia congenita". Neuron8 (5): 891–7. doi:10.1016/0896-6273(92)90203-P. PMID1316765.
McClatchey AI, McKenna-Yasek D, Cros D, et al. (1993). "Novel mutations in families with unusual and variable disorders of the skeletal muscle sodium channel". Nat. Genet.2 (2): 148–52. doi:10.1038/ng1092-148. PMID1338909.
McClatchey AI, Lin CS, Wang J, et al. (1993). "The genomic structure of the human skeletal muscle sodium channel gene". Hum. Mol. Genet.1 (7): 521–7. doi:10.1093/hmg/1.7.521. PMID1339144.
Rojas CV, Wang JZ, Schwartz LS, et al. (1992). "A Met-to-Val mutation in the skeletal muscle Na+ channel alpha-subunit in hyperkalaemic periodic paralysis". Nature354 (6352): 387–9. doi:10.1038/354387a0. PMID1659668.
George AL, Ledbetter DH, Kallen RG, Barchi RL (1991). "Assignment of a human skeletal muscle sodium channel alpha-subunit gene (SCN4A) to 17q23.1-25.3". Genomics9 (3): 555–6. doi:10.1016/0888-7543(91)90425-E. PMID1851726.
Fontaine B, Khurana TS, Hoffman EP, et al. (1990). "Hyperkalemic periodic paralysis and the adult muscle sodium channel alpha-subunit gene". Science250 (4983): 1000–2. doi:10.1126/science.2173143. PMID2173143.
Plassart E, Reboul J, Rime CS, et al. (1994). "Mutations in the muscle sodium channel gene (SCN4A) in 13 French families with hyperkalemic periodic paralysis and paramyotonia congenita: phenotype to genotype correlations and demonstration of the predominance of two mutations". Eur. J. Hum. Genet.2 (2): 110–24. PMID8044656.
Ptáĉek LJ, Tawil R, Griggs RC, et al. (1994). "Sodium channel mutations in acetazolamide-responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis". Neurology44 (8): 1500–3. doi:10.1212/wnl.44.8.1500. PMID8058156.
Heine R, Pika U, Lehmann-Horn F (1993). "A novel SCN4A mutation causing myotonia aggravated by cold and potassium". Hum. Mol. Genet.2 (9): 1349–53. doi:10.1093/hmg/2.9.1349. PMID8242056.