Encyclopedia
calcium voltage-gated channel subunit alpha1 S
- genes
1. Normal Function
The CACNA1S gene provides instructions for making the main piece (subunit) of a structure called a calcium channel. Channels containing the CACNA1S protein are found in muscles used for movement (skeletal muscles). These skeletal muscle calcium channels play a key role in a process called excitation-contraction coupling, by which electrical signals (excitation) trigger muscle tensing (contraction).
Calcium channels made with the CACNA1S subunit are located in the outer membrane of muscle cells, so they can transmit electrical signals from the cell surface to inside the cell. The channels interact with another type of calcium channel called ryanodine receptor 1 (RYR1) channels (produced from the RYR1 gene). RYR1 channels are located in the membrane of a structure inside the cell that stores calcium ions. Signals transmitted by CACNA1S-containing channels turn on (activate) RYR1 channels, which then release calcium ions inside the cells. The resulting increase in calcium ion concentration within muscle cells stimulates muscles to contract, allowing the body to move.
2. Health Conditions Related to Genetic Changes
2.1. Malignant Hyperthermia
CACNA1S gene mutations account for a very small percentage of all cases of malignant hyperthermia. Malignant hyperthermia is a severe reaction to particular anesthetic drugs that are often used during surgery and other invasive procedures. The reaction involves a high fever (hyperthermia), a rapid heart rate, muscle rigidity, breakdown of muscle fibers (rhabdomyolysis), and increased acid levels in the blood and other tissues (acidosis). Complications can be life-threatening without prompt treatment. Researchers have identified several mutations in the CACNA1S gene that are associated with an increased risk of this condition. These mutations replace single amino acids in the CACNA1S protein.
Channels made with the altered CACNA1S proteins likely activate the RYR1 channel improperly in response to certain drugs (particularly some anesthetics and a type of muscle relaxant used during surgery). As a result, large amounts of calcium ions are released from storage within muscle cells. An overabundance of calcium ions activates processes that generate heat (leading to increased body temperature) and produce excess acid (leading to acidosis). An increase in calcium ion concentration also causes skeletal muscles to contract abnormally, which leads to muscle rigidity.
2.2. Hypokalemic Periodic Paralysis
At least 11 mutations in the CACNA1S gene have been identified in people with hypokalemic periodic paralysis, a condition that causes episodes of extreme muscle weakness, usually in the arms and legs. CACNA1S gene mutations cause up to 70 percent of all cases of this disorder.
Mutations in the CACNA1S gene change single protein building blocks (amino acids) used to make the CACNA1S protein, which alters the structure and function of calcium channels in skeletal muscle cells. The altered channels open more slowly than usual, reducing the flow of calcium ions into these cells. This disruption in calcium ion transport prevents muscles from contracting normally. It is unclear precisely how these changes lead to episodes of muscle weakness in people with hypokalemic periodic paralysis.
3. Other Names for This Gene
- CAC1S_HUMAN
- CACH1
- CACN1
- CACNL1A3
- calcium channel, voltage-dependent, L type, alpha 1S subunit
- Cav1.1
- CCHL1A3
- DHPR
- dihydropyridine receptor
- dihydropyridine-sensitive L-type calcium channel alpha-1 subunit
- HOKPP
- HypoKPP
- hypoPP
- MHS5
- Voltage-dependent L-type calcium channel subunit alpha-1S
- voltage-gated calcium channel subunit alpha Cav1.1
This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/gene/cacna1s
References
- Fouad G, Dalakas M, Servidei S, Mendell JR, Van den Bergh P, Angelini C,Alderson K, Griggs RC, Tawil R, Gregg R, Hogan K, Powers PA, Weinberg N, Malonee W, Ptácek LJ. Genotype-phenotype correlations of DHP receptor alpha 1-subunitgene mutations causing hypokalemic periodic paralysis. Neuromuscul Disord. 1997Jan;7(1):33-8.
- Lehmann-Horn F, Jurkat-Rott K, Rüdel R. Periodic paralysis: understandingchannelopathies. Curr Neurol Neurosci Rep. 2002 Jan;2(1):61-9. Review.
- 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, FuYH, Ptácek LJ. Correlating phenotype and genotype in the periodic paralyses.Neurology. 2004 Nov 9;63(9):1647-55.
- Monnier N, Procaccio V, Stieglitz P, Lunardi J. Malignant-hyperthermiasusceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor inskeletal muscle. Am J Hum Genet. 1997 Jun;60(6):1316-25.
- Rosenberg H, Sambuughin N, Riazi S, Dirksen R. Malignant HyperthermiaSusceptibility. 2003 Dec 19 [updated 2020 Jan 16]. In: Adam MP, Ardinger HH,Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews®[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Availablefrom http://www.ncbi.nlm.nih.gov/books/NBK1146/
- Stewart SL, Hogan K, Rosenberg H, Fletcher JE. Identification of theArg1086His mutation in the alpha subunit of the voltage-dependent calcium channel(CACNA1S) in a North American family with malignant hyperthermia. Clin Genet.2001 Mar;59(3):178-84.
- Venance SL, Cannon SC, Fialho D, Fontaine B, Hanna MG, Ptacek LJ,Tristani-Firouzi M, Tawil R, Griggs RC; CINCH investigators. The primary periodicparalyses: diagnosis, pathogenesis and treatment. Brain. 2006 Jan;129(Pt 1):8-17.
- Wang Q, Liu M, Xu C, Tang Z, Liao Y, Du R, Li W, Wu X, Wang X, Liu P, Zhang X,Zhu J, Ren X, Ke T, Wang Q, Yang J. Novel CACNA1S mutation causes autosomaldominant hypokalemic periodic paralysis in a Chinese family. J Mol Med (Berl).2005 Mar;83(3):203-8.
- Weber F, Lehmann-Horn F. Hypokalemic Periodic Paralysis. 2002 Apr 30 [updated 2018 Jul 26]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University ofWashington, Seattle; 1993-2020. Available fromhttp://www.ncbi.nlm.nih.gov/books/NBK1338/
- Yamakage M, Namiki A. Calcium channels--basic aspects of their structure,function and gene encoding; anesthetic action on the channels--a review. Can JAnaesth. 2002 Feb;49(2):151-64. Review.
