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#redirect[[Cav1.1]]
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{{BioPsy}}
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{{DISPLAYTITLE:Ca<sub>v</sub>1.1}}
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{{PBB|geneid=779}}
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'''Ca<sub>v</sub>1.1''' also known as the '''calcium channel, voltage-dependent, L type, alpha 1S subunit''', ('''CACNA1S'''), is a [[protein]] which in humans is encoded by the ''CACNA1S'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: CACNA1S calcium channel, voltage-dependent, L type, alpha 1S subunit| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=779| accessdate = }}</ref> It is also known as '''CACNL1A3''' and the '''dihydropyridine receptor''' (DHPR).
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==Function==
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This gene encodes one of the five subunits of the slowly inactivating [[L-type calcium channel|L-type]] voltage-dependent calcium channel in [[skeletal muscle]] cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility.<ref name="entrez" />
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Ca<sub>v</sub>1.1 is a [[voltage-dependent calcium channel]] found in the [[transverse tubule]] of muscles. In [[skeletal muscle]] it associates with the [[ryanodine receptor]] RyR1 of the [[sarcoplasmic reticulum]] via a mechanical linkage. It senses the [[Membrane potential|voltage]] change caused by the [[end-plate potential]] from nervous stimulation and propagated by sodium channels as [[action potential]]s to the T-tubules. It was previously thought that when the muscle depolarises, the calcium channel opens, allowing calcium in and activating RyR1, which mediates much greater calcium release from the sarcoplasmic reticulum. This is the first part of the process of [[excitation-contraction coupling]], which ultimately causes the muscle to contract. Recent findings suggest that in skeletal muscle (but not heart muscle), calcium entry through Cav1.1 is not required; Cav1.1 undergoes a conformational change which allosterically activates RyR1.<ref name="pmid11726651">{{cite journal | author = Proenza C, O'Brien J, Nakai J, Mukherjee S, Allen PD, Beam KG | title = Identification of a region of RyR1 that participates in allosteric coupling with the alpha(1S) (Ca(V)1.1) II-III loop | journal = J. Biol. Chem. | volume = 277 | issue = 8 | pages = 6530–5 | year = 2002 | month = February | pmid = 11726651 | doi = 10.1074/jbc.M106471200 | url = | issn = }}</ref>
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==Clinical significance==
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In [[hypokalemic periodic paralysis]] (HOKPP), the voltage sensors in domains 2 and 4 of Ca<sub>v</sub>1.1 are mutated (loss-of-function), reducing the availability of the channel to sense depolarisation, and therefore it cannot activate the ryanodine receptor as efficiently. As a result, the muscle cannot contract very well and the patient is paralysed. The condition is hypokalemic because a low extracellular potassium [[ion]] concentration will cause the muscle to repolarise to the [[resting potential]] more quickly, so any calcium conductance that does occur cannot be sustained. It becomes more difficult to reach the threshold at which the muscle can contract, and even if this is reached then the muscle is more prone to relaxing. Because of this, the severity would be reduced if potassium ion concentrations are maintained. In contrast, [[hyperkalemic periodic paralysis]] refers to gain-of-function mutations in sodium channels that maintain muscle depolarisation and therefore are aggravated by ''high'' potassium ion concentrations.<ref name="pmid16075040">{{cite journal | author = Jurkat-Rott K, Lehmann-Horn F | title = Muscle channelopathies and critical points in functional and genetic studies | journal = J. Clin. Invest. | volume = 115 | issue = 8 | pages = 2000–9 | year = 2005 | month = August | pmid = 16075040 | pmc = 1180551 | doi = 10.1172/JCI25525 | url = | issn = }}</ref>
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==Blockers==
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Ca<sub>v</sub>1.1 is [[channel blocker|blocked]] by [[dihydropyridine]].
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==See also==
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* [[Calcium channel]]
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==References==
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{{reflist}}
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==Further reading==
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{{refbegin | 2}}
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*{{cite journal | author=Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J |title=International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels |journal=Pharmacol. Rev. |volume=57 |issue= 4 |pages= 411–25 |year= 2006 |pmid= 16382099 |doi= 10.1124/pr.57.4.5 }}
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*{{cite journal | author=Rotman EI, De Jongh KS, Florio V, ''et al.'' |title=Specific phosphorylation of a COOH-terminal site on the full-length form of the alpha 1 subunit of the skeletal muscle calcium channel by cAMP-dependent protein kinase |journal=J. Biol. Chem. |volume=267 |issue= 23 |pages= 16100–5 |year= 1992 |pmid= 1322891 |doi= }}
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*{{cite journal | author=Röhrkasten A, Meyer HE, Nastainczyk W, ''et al.'' |title=cAMP-dependent protein kinase rapidly phosphorylates serine- 687 of the skeletal muscle receptor for calcium channel blockers |journal=J. Biol. Chem. |volume=263 |issue= 30 |pages= 15325–9 |year= 1988 |pmid= 2844809 |doi= }}
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*{{cite journal | author=Tanabe T, Takeshima H, Mikami A, ''et al.'' |title=Primary structure of the receptor for calcium channel blockers from skeletal muscle |journal=Nature |volume=328 |issue= 6128 |pages= 313–8 |year= 1987 |pmid= 3037387 |doi= 10.1038/328313a0 }}
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*{{cite journal | author=Hogan K, Powers PA, Gregg RG |title=Cloning of the human skeletal muscle alpha 1 subunit of the dihydropyridine-sensitive L-type calcium channel (CACNL1A3) |journal=Genomics |volume=24 |issue= 3 |pages= 608–9 |year= 1995 |pmid= 7713519 |doi= 10.1006/geno.1994.1677 }}
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*{{cite journal | author=Elbaz A, Vale-Santos J, Jurkat-Rott K, ''et al.'' |title=Hypokalemic periodic paralysis and the dihydropyridine receptor (CACNL1A3): genotype/phenotype correlations for two predominant mutations and evidence for the absence of a founder effect in 16 caucasian families |journal=Am. J. Hum. Genet. |volume=56 |issue= 2 |pages= 374–80 |year= 1995 |pmid= 7847370 |doi= | pmc=1801148 }}
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*{{cite journal | author=Boerman RH, Ophoff RA, Links TP, ''et al.'' |title=Mutation in DHP receptor alpha 1 subunit (CACLN1A3) gene in a Dutch family with hypokalaemic periodic paralysis |journal=J. Med. Genet. |volume=32 |issue= 1 |pages= 44–7 |year= 1995 |pmid= 7897626 |doi=10.1136/jmg.32.1.44 | pmc=1050178 }}
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*{{cite journal | author=Gregg RG, Couch F, Hogan K, Powers PA |title=Assignment of the human gene for the alpha 1 subunit of the skeletal muscle DHP-sensitive Ca2+ channel (CACNL1A3) to chromosome 1q31-q32 |journal=Genomics |volume=15 |issue= 1 |pages= 107–12 |year= 1993 |pmid= 7916735 |doi= 10.1006/geno.1993.1017 }}
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*{{cite journal | author=Jurkat-Rott K, Lehmann-Horn F, Elbaz A, ''et al.'' |title=A calcium channel mutation causing hypokalemic periodic paralysis |journal=Hum. Mol. Genet. |volume=3 |issue= 8 |pages= 1415–9 |year= 1995 |pmid= 7987325 |doi=10.1093/hmg/3.8.1415 }}
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*{{cite journal | author=Ptácek LJ, Tawil R, Griggs RC, ''et al.'' |title=Dihydropyridine receptor mutations cause hypokalemic periodic paralysis |journal=Cell |volume=77 |issue= 6 |pages= 863–8 |year= 1994 |pmid= 8004673 |doi=10.1016/0092-8674(94)90135-X }}
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*{{cite journal | author=Drouet B, Garcia L, Simon-Chazottes D, ''et al.'' |title=The gene coding for the alpha 1 subunit of the skeletal dihydropyridine receptor (Cchl1a3 = mdg) maps to mouse chromosome 1 and human 1q32 |journal=Mamm. Genome |volume=4 |issue= 9 |pages= 499–503 |year= 1994 |pmid= 8118099 |doi=10.1007/BF00364784 }}
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*{{cite journal | author=Iles DE, Segers B, Olde Weghuis D, ''et al.'' |title=Refined localization of the alpha 1-subunit of the skeletal muscle L-type voltage-dependent calcium channel (CACNL1A3) to human chromosome 1q32 by in situ hybridization |journal=Genomics |volume=19 |issue= 3 |pages= 561–3 |year= 1994 |pmid= 8188298 |doi=10.1006/geno.1994.1106 }}
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*{{cite journal | author=O'Brien RO, Taske NL, Hansbro PM, ''et al.'' |title=Exclusion of defects in the skeletal muscle specific regions of the DHPR alpha 1 subunit as frequent causes of malignant hyperthermia |journal=J. Med. Genet. |volume=32 |issue= 11 |pages= 913–4 |year= 1996 |pmid= 8592342 |doi=10.1136/jmg.32.11.913 | pmc=1051750 }}
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*{{cite journal | author=Hogan K, Gregg RG, Powers PA |title=The structure of the gene encoding the human skeletal muscle alpha 1 subunit of the dihydropyridine-sensitive L-type calcium channel (CACNL1A3) |journal=Genomics |volume=31 |issue= 3 |pages= 392–4 |year= 1997 |pmid= 8838325 |doi= 10.1006/geno.1996.0066 }}
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*{{cite journal | author=Robinson RL, Monnier N, Wolz W, ''et al.'' |title=A genome wide search for susceptibility loci in three European malignant hyperthermia pedigrees |journal=Hum. Mol. Genet. |volume=6 |issue= 6 |pages= 953–61 |year= 1997 |pmid= 9175745 |doi=10.1093/hmg/6.6.953 }}
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*{{cite journal | author=Monnier N, Procaccio V, Stieglitz P, Lunardi J |title=Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle |journal=Am. J. Hum. Genet. |volume=60 |issue= 6 |pages= 1316–25 |year= 1997 |pmid= 9199552 |doi=10.1086/515454 | pmc=1716149 }}
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*{{cite journal | author=Meyers MB, Puri TS, Chien AJ, ''et al.'' |title=Sorcin associates with the pore-forming subunit of voltage-dependent L-type Ca2+ channels |journal=J. Biol. Chem. |volume=273 |issue= 30 |pages= 18930–5 |year= 1998 |pmid= 9668070 |doi=10.1074/jbc.273.30.18930 }}
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*{{cite journal | author=Morrill JA, Brown RH, Cannon SC |title=Gating of the L-type Ca channel in human skeletal myotubes: an activation defect caused by the hypokalemic periodic paralysis mutation R528H |journal=J. Neurosci. |volume=18 |issue= 24 |pages= 10320–34 |year= 1999 |pmid= 9852570 |doi= }}
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*{{cite journal | author=Protasi F, Paolini C, Nakai J, ''et al.'' |title=Multiple regions of RyR1 mediate functional and structural interactions with alpha(1S)-dihydropyridine receptors in skeletal muscle |journal=Biophys. J. |volume=83 |issue= 6 |pages= 3230–44 |year= 2003 |pmid= 12496092 |doi=10.1016/S0006-3495(02)75325-3 | pmc=1302400 }}
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*{{cite journal | author=Carsana A, Fortunato G, De Sarno C, ''et al.'' |title=Identification of new polymorphisms in the CACNA1S gene |journal=Clin. Chem. Lab. Med. |volume=41 |issue= 1 |pages= 20–2 |year= 2003 |pmid= 12636044 |doi=10.1515/CCLM.2003.004 }}
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}}
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{{refend}}
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==External links==
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* [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=mhs GeneReviews/NCBI/NIH/UW entry on Malignant Hyperthermia Susceptibility]
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* {{MeshName|CACNA1S+protein,+human}}
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{{NLM content}}
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{{Ion channels|g1}}
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[[Category:Ion channels]]
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[[Category:Muscle]]
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[[de:Spannungsabhängiger L-Typ-Calciumkanal]]
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Cav1.1 also known as the calcium channel, voltage-dependent, L type, alpha 1S subunit, (CACNA1S), is a protein which in humans is encoded by the CACNA1S gene.[1] It is also known as CACNL1A3 and the dihydropyridine receptor (DHPR).

FunctionEdit

This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility.[1]

Cav1.1 is a voltage-dependent calcium channel found in the transverse tubule of muscles. In skeletal muscle it associates with the ryanodine receptor RyR1 of the sarcoplasmic reticulum via a mechanical linkage. It senses the voltage change caused by the end-plate potential from nervous stimulation and propagated by sodium channels as action potentials to the T-tubules. It was previously thought that when the muscle depolarises, the calcium channel opens, allowing calcium in and activating RyR1, which mediates much greater calcium release from the sarcoplasmic reticulum. This is the first part of the process of excitation-contraction coupling, which ultimately causes the muscle to contract. Recent findings suggest that in skeletal muscle (but not heart muscle), calcium entry through Cav1.1 is not required; Cav1.1 undergoes a conformational change which allosterically activates RyR1.[2]

Clinical significanceEdit

In hypokalemic periodic paralysis (HOKPP), the voltage sensors in domains 2 and 4 of Cav1.1 are mutated (loss-of-function), reducing the availability of the channel to sense depolarisation, and therefore it cannot activate the ryanodine receptor as efficiently. As a result, the muscle cannot contract very well and the patient is paralysed. The condition is hypokalemic because a low extracellular potassium ion concentration will cause the muscle to repolarise to the resting potential more quickly, so any calcium conductance that does occur cannot be sustained. It becomes more difficult to reach the threshold at which the muscle can contract, and even if this is reached then the muscle is more prone to relaxing. Because of this, the severity would be reduced if potassium ion concentrations are maintained. In contrast, hyperkalemic periodic paralysis refers to gain-of-function mutations in sodium channels that maintain muscle depolarisation and therefore are aggravated by high potassium ion concentrations.[3]

BlockersEdit

Cav1.1 is blocked by dihydropyridine.

See alsoEdit

ReferencesEdit

  1. 1.0 1.1 Entrez Gene: CACNA1S calcium channel, voltage-dependent, L type, alpha 1S subunit.
  2. Proenza C, O'Brien J, Nakai J, Mukherjee S, Allen PD, Beam KG (February 2002). Identification of a region of RyR1 that participates in allosteric coupling with the alpha(1S) (Ca(V)1.1) II-III loop. J. Biol. Chem. 277 (8): 6530–5.
  3. Jurkat-Rott K, Lehmann-Horn F (August 2005). Muscle channelopathies and critical points in functional and genetic studies. J. Clin. Invest. 115 (8): 2000–9.

Further readingEdit

  • Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J (2006). International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels. Pharmacol. Rev. 57 (4): 411–25.
  • Rotman EI, De Jongh KS, Florio V, et al. (1992). Specific phosphorylation of a COOH-terminal site on the full-length form of the alpha 1 subunit of the skeletal muscle calcium channel by cAMP-dependent protein kinase. J. Biol. Chem. 267 (23): 16100–5.
  • Röhrkasten A, Meyer HE, Nastainczyk W, et al. (1988). cAMP-dependent protein kinase rapidly phosphorylates serine- 687 of the skeletal muscle receptor for calcium channel blockers. J. Biol. Chem. 263 (30): 15325–9.
  • Tanabe T, Takeshima H, Mikami A, et al. (1987). Primary structure of the receptor for calcium channel blockers from skeletal muscle. Nature 328 (6128): 313–8.
  • Hogan K, Powers PA, Gregg RG (1995). Cloning of the human skeletal muscle alpha 1 subunit of the dihydropyridine-sensitive L-type calcium channel (CACNL1A3). Genomics 24 (3): 608–9.
  • Elbaz A, Vale-Santos J, Jurkat-Rott K, et al. (1995). Hypokalemic periodic paralysis and the dihydropyridine receptor (CACNL1A3): genotype/phenotype correlations for two predominant mutations and evidence for the absence of a founder effect in 16 caucasian families. Am. J. Hum. Genet. 56 (2): 374–80.
  • Boerman RH, Ophoff RA, Links TP, et al. (1995). Mutation in DHP receptor alpha 1 subunit (CACLN1A3) gene in a Dutch family with hypokalaemic periodic paralysis. J. Med. Genet. 32 (1): 44–7.
  • Gregg RG, Couch F, Hogan K, Powers PA (1993). Assignment of the human gene for the alpha 1 subunit of the skeletal muscle DHP-sensitive Ca2+ channel (CACNL1A3) to chromosome 1q31-q32. Genomics 15 (1): 107–12.
  • Jurkat-Rott K, Lehmann-Horn F, Elbaz A, et al. (1995). A calcium channel mutation causing hypokalemic periodic paralysis. Hum. Mol. Genet. 3 (8): 1415–9.
  • Ptácek LJ, Tawil R, Griggs RC, et al. (1994). Dihydropyridine receptor mutations cause hypokalemic periodic paralysis. Cell 77 (6): 863–8.
  • Drouet B, Garcia L, Simon-Chazottes D, et al. (1994). The gene coding for the alpha 1 subunit of the skeletal dihydropyridine receptor (Cchl1a3 = mdg) maps to mouse chromosome 1 and human 1q32. Mamm. Genome 4 (9): 499–503.
  • Iles DE, Segers B, Olde Weghuis D, et al. (1994). Refined localization of the alpha 1-subunit of the skeletal muscle L-type voltage-dependent calcium channel (CACNL1A3) to human chromosome 1q32 by in situ hybridization. Genomics 19 (3): 561–3.
  • O'Brien RO, Taske NL, Hansbro PM, et al. (1996). Exclusion of defects in the skeletal muscle specific regions of the DHPR alpha 1 subunit as frequent causes of malignant hyperthermia. J. Med. Genet. 32 (11): 913–4.
  • Hogan K, Gregg RG, Powers PA (1997). The structure of the gene encoding the human skeletal muscle alpha 1 subunit of the dihydropyridine-sensitive L-type calcium channel (CACNL1A3). Genomics 31 (3): 392–4.
  • Robinson RL, Monnier N, Wolz W, et al. (1997). A genome wide search for susceptibility loci in three European malignant hyperthermia pedigrees. Hum. Mol. Genet. 6 (6): 953–61.
  • Monnier N, Procaccio V, Stieglitz P, Lunardi J (1997). Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am. J. Hum. Genet. 60 (6): 1316–25.
  • Meyers MB, Puri TS, Chien AJ, et al. (1998). Sorcin associates with the pore-forming subunit of voltage-dependent L-type Ca2+ channels. J. Biol. Chem. 273 (30): 18930–5.
  • Morrill JA, Brown RH, Cannon SC (1999). Gating of the L-type Ca channel in human skeletal myotubes: an activation defect caused by the hypokalemic periodic paralysis mutation R528H. J. Neurosci. 18 (24): 10320–34.
  • Protasi F, Paolini C, Nakai J, et al. (2003). Multiple regions of RyR1 mediate functional and structural interactions with alpha(1S)-dihydropyridine receptors in skeletal muscle. Biophys. J. 83 (6): 3230–44.
  • Carsana A, Fortunato G, De Sarno C, et al. (2003). Identification of new polymorphisms in the CACNA1S gene. Clin. Chem. Lab. Med. 41 (1): 20–2.

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