This gene encodes an alpha-1 subunit of a voltage-dependentcalcium channel. Calcium channels mediate the influx of calciumions (Ca2+) into thecell upon membrane polarization (seemembrane potential andcalcium in biology).[7]
The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta and beta subunits in a 1:1:1 ratio. The S3-S4 linkers of Cav1.2 determine the gating phenotype and modulated gating kinetics of the channel.[8] Cav1.2 is widely expressed in thesmooth muscle,pancreatic cells,fibroblasts, andneurons.[9][10] However, it is particularly important and well known for its expression in the heart where it mediates L-type currents, which causes calcium-induced calcium release from the ER Stores viaryanodine receptors. It depolarizes at -30mV and helps define the shape of the action potential incardiac and smooth muscle.[8] The protein encoded by this gene binds to and is inhibited bydihydropyridine.[11] In the arteries of the brain, high levels of calcium in mitochondria elevates activity of nuclear factor kappa BNF-κB and transcription of CACNA1c and functional Cav1.2 expression increases.[12] Cav1.2 also regulates levels ofosteoprotegerin.[13]
The activity of CaV1.2 channels is tightly regulated by the Ca2+ signals they produce. An increase in intracellular Ca2+ concentration implicated in Cav1.2 facilitation, a form of positive feedback called Ca2+-dependent facilitation, that amplifies Ca2+ influx. In addition, increasing influx intracellular Ca2+ concentration has implicated to exert the opposite effect Ca2+ dependent inactivation.[15] These activation and inactivation mechanisms both involve Ca2+ binding to calmodulin (CaM) in the IQ domain in the C-terminal tail of these channels.[16] Cav1.2 channels are arranged in cluster of eight, on average, in the cell membrane. When calcium ions bind to calmodulin, which in turn binds to a Cav1.2 channel, it allows the Cav1.2 channels within a cluster to interact with each other.[17] This results in channels working cooperatively when they open at the same time to allow more calcium ions to enter and then close together to allow the cell to relax.[17]
Due to simplicity only two Calcium channels are shown to depict clustering. When depolarization occurs, calcium ions flow through the channel and some bind to Calmodulin. The Calcium/Calmodulin binding to the C-terminal pre-IQ domain of the Cav1.2 channel promotes interaction between channels that are beside each other.
Timothy Syndrome is a rareautosomal dominant disorder caused by rare heterozygous missense (non-synonymous)variants (mutations) in CACNA1C.[18] These variants are typically called 'gain of function' variants as their functional impact alters the excitation of the Cav1.2 channel.[19] The most frequent causative pathogenic variants for Timothy syndrome are p.G406R and p.G402S. There are two subtypes of Timothy syndrome: Type 1 and Type 2.[20] Timothy Syndrome Type 1 is caused by p.G406R inexon 8, with individuals presenting withprolonged QT, cardiac arrhythmia, neurodevelopmental delays,syndactyly,hypoglycaemia andhypotonia.[21] Individuals with Type 2 predominantly harbour p.G406R too, but, due to alternative splicing, this variant occurs in exon 8A. Timothy syndrome Type 2 has a similarphenotype to type 1 but also exhibitship dysplasia.[22] Further variants have been linked to both syndromes.
Alongside Timothy Syndrome,high-penetrance missenseCACNA1C variants have also been noted in patients withLongQT Type 8, predominantly with no further extra-cardiac symptoms presenting.[23] LongQT Type 8 is a condition which is categorised by a prolongedQT interval,syncope and ventriculararrhythmias.[24] Although extra-cardiac features are not common, this could be due to underreporting.
AlthoughCACNA1C variants have been identified inBrugada Syndrome patients, the evidence for variants (such as p.A39V and p.G490R) causing genetic aetiology is disputed.[25][26][27] The link between Brugada Syndrome andCACNA1C variants is limited and predominantly consists of single-family cases with limiteddisease segregation.[28][29] There is currently insufficient evidence for the impact ofCACNA1C variants on Brugada Syndrome, as currently corroborated by theGenomics England Panel App.[30][31]
Large-scale genetic analyses have shown the possibility thatCACNA1C is associated withbipolar disorder[32] and subsequently also withschizophrenia.[33][34][35] Also, aCACNA1C risk allele has been associated to a disruption in brain connectivity in patients with bipolar disorder, while not or only to a minor degree, in their unaffected relatives or healthy controls.[36] In a first study in Indian population, the Schizophrenia associatedGenome-wide association study (GWAS) single nucelotide polymorphism (SNP) was found not to be associated with the disease. Furthermore, the main effect of rs1006737 was found to be associated with spatial abilityefficiency scores. Subjects with genotypes carrying the risk allele of rs1006737 (G/A and A/A) were found to have higher spatial ability efficiency scores as compared to those with the G/G genotype. While in healthy controls those with G/A and A/A genotypes were found to have higher spatial memory processing speed scores than those with G/G genotypes, the former had lower scores than the latter in schizophrenia subjects. In the same study the genotypes with the risk allele of rs1006737 namely A/A was associated with a significantly lower Align rank transformed Abnormal and involuntary movement scale (AIMS) scores ofTardive dyskinesia(TD).[37]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Lacerda AE, Kim HS, Ruth P, Perez-Reyes E, Flockerzi V, Hofmann F, Birnbaumer L, Brown AM (Aug 1991). "Normalization of current kinetics by interaction between the alpha 1 and beta subunits of the skeletal muscle dihydropyridine-sensitive Ca2+ channel".Nature.352 (6335):527–30.Bibcode:1991Natur.352..527L.doi:10.1038/352527a0.PMID1650913.S2CID4246540.
^Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J (Dec 2005). "International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels".Pharmacological Reviews.57 (4):411–25.doi:10.1124/pr.57.4.5.PMID16382099.S2CID10386627.
^Berger SM, Bartsch D (Aug 2014). "The role of L-type voltage-gated calcium channels Cav1.2 and Cav1.3 in normal and pathological brain function".Cell and Tissue Research.357 (2):463–76.doi:10.1007/s00441-014-1936-3.PMID24996399.S2CID15914718.
^Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph RM, Condouris K, Tager-Flusberg H, Priori SG, Sanguinetti MC, Keating MT (October 2004). "Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism".Cell.119 (1):19–31.doi:10.1016/j.cell.2004.09.011.PMID15454078.
^Hiippala A, Tallila J, Myllykangas S, Koskenvuo JW, Alastalo TP (March 2015). "Expanding the phenotype of Timothy syndrome type 2: an adolescent with ventricular fibrillation but normal development".American Journal of Medical Genetics. Part A.167A (3):629–634.doi:10.1002/ajmg.a.36924.PMID25691416.
^Sepp R, Hategan L, Bácsi A, Cseklye J, Környei L, Borbás J, Széll M, Forster T, Nagy I, Hegedűs Z (March 2017). "Timothy syndrome 1 genotype without syndactyly and major extracardiac manifestations".American Journal of Medical Genetics. Part A.173 (3):784–789.doi:10.1002/ajmg.a.38084.PMID28211989.
^Fukuyama M, Wang Q, Kato K, Ohno S, Ding WG, Toyoda F, Itoh H, Kimura H, Makiyama T, Ito M, Matsuura H, Horie M (December 2014). "Long QT syndrome type 8: novel CACNA1C mutations causing QT prolongation and variant phenotypes".Europace.16 (12):1828–1837.doi:10.1093/europace/euu063.PMID24728418.
^Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC, Aizawa Y, Guerchicoff A, Pfeiffer R, Oliva A, Wollnik B, Gelber P, Bonaros EP, Burashnikov E, Wu Y, Sargent JD, Schickel S, Oberheiden R, Bhatia A, Hsu LF, Haïssaguerre M, Schimpf R, Borggrefe M, Wolpert C (January 2007). "Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death".Circulation.115 (4):442–449.doi:10.1161/CIRCULATIONAHA.106.668392.PMID17224476.
^Novelli V, Memmi M, Malovini A, Mazzanti A, Liu N, Yanfei R, Bongianino R, Denegri M, Monteforte N, Bloise R, Morini M, Napolitano C (May 2022). "Role of CACNA1C in Brugada syndrome: Prevalence and phenotype of probands referred for genetic testing".Heart Rhythm.19 (5):798–806.doi:10.1016/j.hrthm.2021.12.032.PMID34999275.
^Punchaichira TJ, Kukshal P, Bhatia T, Deshpande SN (2023). "Effect of rs1108580 of DBH and rs1006737 of CACNA1C on Cognition and Tardive Dyskinesia in a North Indian Schizophrenia Cohort".Molecular Neurobiology.60 (12):6826–6839.doi:10.1007/s12035-023-03496-4.PMID37493923.S2CID260162784.
Kempton MJ, Ruberto G, Vassos E, Tatarelli R, Girardi P, Collier D, Frangou S (Dec 2009). "Effects of the CACNA1C risk allele for bipolar disorder on cerebral gray matter volume in healthy individuals".The American Journal of Psychiatry.166 (12):1413–4.doi:10.1176/appi.ajp.2009.09050680.PMID19952088.
Powers PA, Gregg RG, Hogan K (Sep 1992). "Linkage mapping of the human gene for the alpha 1 subunit of the cardiac DHP-sensitive Ca2+ channel (CACNL1A1) to chromosome 12p13.2-pter using a dinucleotide repeat".Genomics.14 (1):206–7.doi:10.1016/S0888-7543(05)80312-X.PMID1330882.
Sun W, McPherson JD, Hoang DQ, Wasmuth JJ, Evans GA, Montal M (Dec 1992). "Mapping of a human brain voltage-gated calcium channel to human chromosome 12p13-pter".Genomics.14 (4):1092–4.doi:10.1016/S0888-7543(05)80135-1.PMID1335957.
Powers PA, Gregg RG, Lalley PA, Liao M, Hogan K (Jul 1991). "Assignment of the human gene for the alpha 1 subunit of the cardiac DHP-sensitive Ca2+ channel (CCHL1A1) to chromosome 12p12-pter".Genomics.10 (3):835–9.doi:10.1016/0888-7543(91)90471-P.PMID1653763.
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