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SCN4A gene
URL of this page: https://medlineplus.gov/genetics/gene/scn4a/

SCN4A gene

sodium voltage-gated channel alpha subunit 4

Normal Function

The SCN4A gene belongs to a family of genes that provide instructions for making sodium channels. These channels, which transport positively charged sodium atoms (sodium ions) into cells, play a key role in a cell's ability to generate and transmit electrical signals.

The SCN4A gene provides instructions for making a critical part (the alpha subunit) of sodium channels that are abundant in muscles used for movement (skeletal muscles). For the body to move, these muscles must tense (contract) and relax in a coordinated way. Muscle contractions are triggered by the flow of ions, including sodium, into skeletal muscle cells. Channels made with the SCN4A protein control the flow of sodium ions into these cells.

Health Conditions Related to Genetic Changes

Hyperkalemic periodic paralysis

More than 14 variants (also known as mutations) in the SCN4A gene have been found to cause hyperkalemic periodic paralysis, a condition that causes episodes of extreme muscle weakness that are often associated with high levels of potassium in the blood (hyperkalemia). The variants change single building blocks (amino acids) in the SCN4A protein, which alters the structure and function of sodium channels in skeletal muscle cells. These changes delay the closing of channels made with the SCN4A protein or prevent the channels from staying closed. As a result, sodium ions continue flowing into muscle cells abnormally. This increase in sodium ions triggers the release of potassium from muscle cells, which causes more sodium channels to open and stimulates the flow of even more sodium ions into these cells. These changes in ion transport reduce the ability of skeletal muscles to contract, leading to episodes of muscle weakness or paralysis.

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Hypokalemic periodic paralysis

At least nine variants in the SCN4A gene have been identified in people with hypokalemic periodic paralysis, a condition that causes episodes of extreme muscle weakness that are associated with low levels of potassium in the blood (hypokalemia). Variants in the SCN4A gene account for about 10 percent of all cases of this condition. Each of the known variants changes a single amino acid in the SCN4A protein, which alters the structure and function of sodium channels in skeletal muscle cells. The abnormal channels change the normal flow of sodium ions, which prevents muscles from contracting normally. Low potassium levels also contribute to this problem. Because muscle contraction is needed for movement, these changes in ion transport lead to long-lasting episodes of severe muscle weakness.

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Paramyotonia congenita

At least 28 variants in the SCN4A gene are known to cause paramyotonia congenita, a muscle disease characterized by episodes of sustained muscle tensing (myotonia) that prevent muscles from relaxing normally. The SCN4A gene variants that cause this condition each change a single amino acid in the SCN4A protein, which alters the structure and function of sodium channels in skeletal muscle cells. The most common genetic changes replace the amino acid arginine with one of several other amino acids at protein position 1448. 

Variants delay the closing of channels made with the SCN4A protein and, once the channels are closed, cause them to open again too quickly. These changes increase the flow of sodium ions into skeletal muscle cells. An influx of extra sodium ions triggers prolonged muscle contractions, which underlie the episodes of myotonia characteristic of paramyotonia congenita. Muscles with sustained high levels of sodium ions may become unable to contract at all, resulting in attacks of muscle weakness. Additionally, the effects of SCN4A gene variants on the altered ion channels may be increased by cold temperatures, which may help explain why signs and symptoms can be triggered by exposure to cold.


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Potassium-aggravated myotonia

Several variants  in the SCN4A gene result in potassium-aggravated myotonia, a condition that causes episodes of myotonia that prevent muscles from relaxing. The resulting muscle stiffness may be triggered (aggravated) by eating potassium-rich foods, such as bananas and potatoes. 

The most common genetic changes associated with potassium-aggravated myotonia replace the amino acid glycine with one of several other amino acids at position 1306 in the SCN4A protein. These variants delay the closing of channels made with the SCN4A protein, which increases the flow of sodium ions into skeletal muscle cells. When excess potassium is present in the body, which occurs after eating potassium-rich foods, even more sodium ions flow into skeletal muscle cells in order to maintain a proper balance of calcium and potassium. These changes in ion transport trigger prolonged muscle contractions, which underlie the muscle stiffness characteristic of potassium-aggravated myotonia.

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Congenital myasthenic syndrome

MedlinePlus Genetics provides information about Congenital myasthenic syndrome

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Other Names for This Gene

  • Na(V)1.4
  • Nav1.4
  • SCN4A_HUMAN
  • skeletal muscle voltage-dependent sodium channel type IV alpha subunit
  • SkM1
  • sodium channel, voltage gated, type IV alpha subunit
  • sodium channel, voltage-gated, type IV, alpha
  • sodium channel, voltage-gated, type IV, alpha subunit
  • voltage-gated sodium channel type 4 alpha

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

  • Burge JA, Hanna MG. Novel insights into the pathomechanisms of skeletal muscle channelopathies. Curr Neurol Neurosci Rep. 2012 Feb;12(1):62-9. doi: 10.1007/s11910-011-0238-3. Citation on PubMed
  • Carle T, Lhuillier L, Luce S, Sternberg D, Devuyst O, Fontaine B, Tabti N. Gating defects of a novel Na+ channel mutant causing hypokalemic periodic paralysis. Biochem Biophys Res Commun. 2006 Sep 22;348(2):653-61. doi: 10.1016/j.bbrc.2006.07.101. Epub 2006 Jul 28. Citation on PubMed
  • Groome JR, Fujimoto E, Ruben PC. K-aggravated myotonia mutations at residue G1306 differentially alter deactivation gating of human skeletal muscle sodium channels. Cell Mol Neurobiol. 2005 Nov;25(7):1075-92. doi: 10.1007/s10571-005-8057-1. Citation on PubMed
  • Jurkat-Rott K, Holzherr B, Fauler M, Lehmann-Horn F. Sodium channelopathies of skeletal muscle result from gain or loss of function. Pflugers Arch. 2010 Jul;460(2):239-48. doi: 10.1007/s00424-010-0814-4. Epub 2010 Mar 17. Citation on PubMed or Free article on PubMed Central
  • Jurkat-Rott K, Weber MA, Fauler M, Guo XH, Holzherr BD, Paczulla A, Nordsborg N, Joechle W, Lehmann-Horn F. K+-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion channel leaks. Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):4036-41. doi: 10.1073/pnas.0811277106. Epub 2009 Feb 18. Citation on PubMed or Free article on PubMed Central
  • Maggi L, Bonanno S, Altamura C, Desaphy JF. Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy. Cells. 2021 Jun 16;10(6):1521. doi: 10.3390/cells10061521. Citation on PubMed
  • Maggi L, Brugnoni R, Canioni E, Tonin P, Saletti V, Sola P, Piccinelli SC, Colleoni L, Ferrigno P, Pini A, Masson R, Manganelli F, Lietti D, Vercelli L, Ricci G, Bruno C, Tasca G, Pizzuti A, Padovani A, Fusco C, Pegoraro E, Ruggiero L, Ravaglia S, Siciliano G, Morandi L, Dubbioso R, Mongini T, Filosto M, Tramacere I, Mantegazza R, Bernasconi P. Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients. Front Neurol. 2020 Jul 29;11:646. doi: 10.3389/fneur.2020.00646. eCollection 2020. Citation on PubMed
  • Miller TM, Dias da Silva MR, Miller HA, Kwiecinski H, Mendell JR, Tawil R, McManis P, Griggs RC, Angelini C, Servidei S, Petajan J, Dalakas MC, Ranum LP, Fu YH, Ptacek LJ. Correlating phenotype and genotype in the periodic paralyses. Neurology. 2004 Nov 9;63(9):1647-55. doi: 10.1212/01.wnl.0000143383.91137.00. Citation on PubMed
  • Sun J, Luo S, Suetterlin KJ, Song J, Huang J, Zhu W, Xi J, Zhou L, Lu J, Lu J, Zhao C, Hanna MG, Mannikko R, Matthews E, Qiao K. Clinical and genetic spectrum of a Chinese cohort with SCN4A gene mutations. Neuromuscul Disord. 2021 Sep;31(9):829-838. doi: 10.1016/j.nmd.2021.03.014. Epub 2021 Apr 15. Citation on PubMed
  • Tamaoka A. Paramyotonia congenita and skeletal sodium channelopathy. Intern Med. 2003 Sep;42(9):769-70. doi: 10.2169/internalmedicine.42.769. No abstract available. Citation on PubMed
  • Tsujino A, Maertens C, Ohno K, Shen XM, Fukuda T, Harper CM, Cannon SC, Engel AG. Myasthenic syndrome caused by mutation of the SCN4A sodium channel. Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7377-82. doi: 10.1073/pnas.1230273100. Epub 2003 May 23. Citation on PubMed or Free article on PubMed Central
  • Vicart S, Sternberg D, Fontaine B, Meola G. Human skeletal muscle sodium channelopathies. Neurol Sci. 2005 Oct;26(4):194-202. doi: 10.1007/s10072-005-0461-x. Citation on PubMed
  • Weber F, Lehmann-Horn F. Hypokalemic Periodic Paralysis. 2002 Apr 30 [updated 2018 Jul 26]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK1338/ Citation on PubMed
  • Weber F. Hyperkalemic Periodic Paralysis. 2003 Jul 18 [updated 2021 Jul 1]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK1496/ Citation on PubMed

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