Alternative titles; symbols
HGNC Approved Gene Symbol: CACNA1D
SNOMEDCT: 770784003;
Cytogenetic location: 3p21.1 Genomic coordinates (GRCh38): 3:53,494,611-53,813,733 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.1 | Primary aldosteronism, seizures, and neurologic abnormalities | 615474 | Autosomal dominant | 3 |
| Sinoatrial node dysfunction and deafness | 614896 | Autosomal recessive | 3 |
Voltage-sensitive Ca(2+) channels play an important role in regulating hormone and neurotransmitter release, muscle contraction, and a large number of other cellular functions. The voltage-sensitive Ca(2+) channels are multisubunit proteins. For example, in skeletal muscle the complex has 4 distinct subunits, alpha-1 (170 kD), alpha-2/delta (175 kD), beta (52 kD), and gamma (32 kD). The alpha-1 and beta subunits are members of gene families; cDNAs encoding 4 structurally related alpha-1 subunits and 2 beta subunits have been reported (Tsien et al., 1991). The alpha-1 subunits were termed the skeletal muscle, heart, brain, and neuroendocrine/brain isoforms. On the basis of their kinetics and pharmacology, 4 types of Ca(2+) currents have been described. The Ca(2+) channel activity associated with the skeletal muscle, heart, and neuroendocrine/brain alpha-1 subunit isoforms is inhibited by dihydropyridine (DHP) drugs, indicating that these represent L-type currents. By contrast, the activity of the brain isoform is not inhibited by dihydropyridine drugs and thus may represent a P-type current.
Williams et al. (1992) isolated a cDNA corresponding to the human alpha-1D subunit from a human neuroblastoma cell line. The deduced 2,161-amino acid protein has a calculated molecular mass of 245 kD. The predicted structure consists of 4 repeating domains, each comprising 5 hydrophobic segments. There was evidence of alternative splicing.
Seino et al. (1992) independently isolated cDNA from pancreatic beta cells that encodes the human neuroendocrine/brain-type alpha-1 subunit.
Baig et al. (2011) observed expression of the Cacna1d alternatively spliced exon 8B in inner hair cell and organ of Corti preparations from adult mouse cochlea, whereas exon 8A was rare or absent. A similar expression pattern was found in mouse sinoatrial node preparations.
Chin et al. (1991) used a rat brain cDNA probe to localize the alpha-1 subunit of neuronal DHP-sensitive L-type calcium channels in the mouse and human genomes. The gene was assigned to mouse chromosome 14 by Southern analysis of Chinese hamster/mouse somatic cell hybrid DNAs. It was mapped to a position 7.5 cM proximal to Np-1 by Southern analysis of DNAs from an intersubspecies cross. Southern analysis of human/rodent somatic cell hybrids indicated that the CCHL1A2 gene maps to human chromosome 3. Because of the homology between proximal mouse chromosome 14 and human 3p, Chin et al. (1991) suggested that the CCHL1A2 gene may be on 3p.
By fluorescence in situ hybridization, Seino et al. (1992) mapped the CACNL1A2 gene to 3p14.3. Seino et al. (1992) suggested that the alpha-1 subunit gene termed brain L-type calcium channel subunit mapped to 3p by Chin et al. (1991) may in fact have been the neuroendocrine/brain isoform rather than the brain isoform described by Mori et al. (1991). The fact that it was DHP-sensitive supports this conclusion.
Gross (2016) mapped the CACNA1D gene to chromosome 3p21.1 based on an alignment of the CACNA1D sequence (GenBank AF055575) with the genomic sequence (GRCh38).
By studies in Xenopus oocytes, Williams et al. (1992) found that the alpha-1D subunit mediated DHP-sensitive, high voltage-activated, long-lasting calcium channel activity. Significant expression was dependent on the coexpression of a beta-2 (CACNB2; 600003) subunit and was enhanced by coexpression of an alpha-2b (CACNA2D1; 114204) subunit.
Self-biting and other self-injurious behaviors occur in a number of disorders. They are most commonly seen in developmentally disabled individuals with severe mental retardation or autism. These behaviors also occur in specific neurogenetic disorders such as Lesch-Nyhan syndrome (308000), Rett syndrome (312750), and neuroacanthocytosis (200150). Jinnah et al. (1999) studied an L-type calcium channel activator that increases calcium fluxes in response to depolarizing stimuli and had been reported to produce, in rodents, characteristic motor abnormalities, including self-injurious behavior. Jinnah et al. (1999) showed that this L-type calcium channel agonist reliably provoked self-biting and self-injurious behavior under certain conditions in mice. The self-biting provoked by the agent could be inhibited by pretreating the mice with dihydropyridine L-type calcium channel antagonists such as nifedipine. However, self-biting was not inhibited by nondihydropyridine antagonists, including verapamil.
Davare et al. (2001) found that the beta-2 adrenergic receptor (109690) is directly associated with one of its ultimate effectors, CACNA1D. This complex also contains a G protein, an adenylyl cyclase (see 103070), cAMP-dependent kinase (see 601639), and the counterbalancing phosphatase PP2A (see 605997). Davare et al. (2001) used electrophysiologic recordings from hippocampal neurons to demonstrate highly localized signal transduction from the receptor to the channel. The assembly of this signaling complex provides a mechanism that ensures specific and rapid signaling by a G protein-coupled receptor.
Pennartz et al. (2002) demonstrated a diurnal modulation of calcium current mediated through L-type calcium channels in suprachiasmatic neurons. This current strongly contributes to the generation of spontaneous oscillations in membrane potential, which occur selectively during daytime and are tightly coupled to spike generation. Thus, Pennartz et al. (2002) concluded that day-night modulation of calcium current is a central step in transducing the intracellular cycling of molecular clocks (circadian rhythm) to the rhythm in spontaneous firing rate.
Liu et al. (2010) combined electrophysiology to characterize channel regulation with optical fluorescence resonance energy transfer (FRET) sensor determination of free-apoCaM (CALM1; 114180) concentration in live cells. This approach translates quantitative CaM biochemistry from the traditional test-tube context into the realm of functioning holochannels within intact cells. From this perspective, Liu et al. (2010) found that long splice forms of Ca(v)1.3 (CACNA1D) and Ca(v)1.4 (CACNA1F; 300110) channels include a distal carboxy tail that resembles an enzyme competitive inhibitor that retunes channel affinity for apoCaM such that natural CaM variations affect the strength of Ca(2+) feedback modulation. Given the ubiquity of these channels, the connection between ambient CaM levels and Ca(2+) entry through channels is broadly significant for Ca(2+) homeostasis.
Sinoatrial Node Dysfunction and Deafness
In 2 consanguineous Pakistani families with sinoatrial node dysfunction and deafness (SANDD; 614896), Baig et al. (2011) identified homozygosity for a 3-bp insertion in the CACNA1D gene (114206.0001) that segregated with disease in both families. The authors noted the striking similarity between this human channelopathy and the Cacna1d knockout mouse phenotype.
Primary Aldosteronism, Seizures, and Neurologic Abnormalities
Scholl et al. (2013) sequenced the candidate gene CACNA1D in 100 unrelated individuals with unexplained early-onset primary aldosteronism and identified 2 girls with de novo heterozygous gain-of-function missense mutations, G403D (114206.0002) and I770M (114206.0003). In addition to hypertension, both patients had seizures and neurologic abnormalities (PASNA; 615474).
Scholl et al. (2013) identified 5 somatic mutations, 4 altering G403 and 1 altering I770, in CACNA1D among 43 adrenal aldosterone-producing adenomas (APAs) without mutated KCNJ5 (600734). The altered residues lie in the S6 segments that line the channel pore. Both alterations result in channel activation at less depolarized potentials; G403 alterations also impair channel inactivation. Scholl et al. (2013) concluded that these effects could cause increased Ca(2+) influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa.
Azizan et al. (2013) performed exome sequencing of 10 zona glomerulosa-like APAs and identified 9 with somatic mutations in either ATP1A1 (182310), encoding the Na+/K+ ATPase alpha-1 subunit, or CACNA1D. The ATP1A1 mutations all caused inward leak currents under physiologic conditions, and the CACNA1D mutations induced a shift of voltage-dependent gating to more negative voltages, suppressed inactivation, or increased currents. Many APAs with these mutations were less than 1 cm in diameter and had been overlooked on conventional adrenal imaging. Azizan et al. (2013) concluded that recognition of the distinct genotype and phenotype for this subset of APAs could facilitate diagnosis.
Platzer et al. (2000) generated Cacna1d-deficient mice that were viable with no major disturbances of glucose metabolism. Cacna1d-deficient mice were deaf due to the complete absence of L-type currents in cochlear inner hair cells and degeneration of outer and inner hair cells. In wildtype controls, Cacna1d-mediated currents showed low activation thresholds and slow inactivation kinetics. Electrocardiogram recordings revealed sinoatrial node dysfunction (bradycardia and arrhythmia) in Cacna1d-deficient mice. The authors concluded that CACNA1D can form L-type calcium channels with negative activation thresholds essential for normal auditory function and control of cardiac pacemaker activity.
In affected individuals from 2 unrelated consanguineous Pakistani families with congenital deafness and bradycardia (SANDD; 614896), Baig et al. (2011) identified homozygosity for a 3-bp insertion (1208_1209insGGG) in the alternatively spliced exon 8B of the CACNA1D gene, resulting in the in-frame insertion of a gly residue (403_404insGly) in the cytoplasmic end of the evolutionarily highly conserved inner pore-lining S6 helix in domain 1. Homozygosity for the mutation segregated completely with disease in both families. Whole-cell patch-clamp recordings in transfected tsA-201 cells demonstrated that the mutant channels are unable to conduct Ca(2+) currents and have abnormal voltage-dependent gating.
In a 3-year-old girl of European ancestry with primary aldosteronism, seizures, and neurologic abnormalities (PASNA; 615474), Scholl et al. (2013) identified heterozygosity for a de novo c.1208G-A transition in exon 8B of the CACNA1D gene, resulting in a gly403-to-asp (G403D) substitution at a highly conserved residue within the S6 segments that line the channel pore. The mutation was not present in her unaffected parents and had not been reported in SNP or exome databases. Whole-cell patch-clamp recordings in HEK293 cells showed channel activation with the G403D mutant at less depolarized potentials than with wildtype, as well as impaired inactivation. In addition, increased current density with the G403D mutant was observed.
In a 10-year-old African American girl with primary aldosteronism, seizures, and neurologic abnormalities (615474), Scholl et al. (2013) identified heterozygosity for a de novo c.2310C-G transversion in exon 8A of the CACNA1D gene, resulting in an ile770-to-met (I770M) substitution at a highly conserved residue within the S6 segments that line the channel pore. The mutation was not present in her unaffected parents and had not been reported in SNP or exome databases. Whole-cell patch-clamp recordings in HEK293 cells showed channel activation with the I770M mutant at less depolarized potentials than with wildtype. In addition, increased current density with the I770M mutant was observed.
Azizan, E. A. B., Poulsen, H., Tuluc, P., Zhou, J., Clausen, M. V., Lieb, A., Maniero, C., Garg, S., Bochukova, E. G., Zhao, W., Shaikh, L. H., Brighton, C. A., and 21 others. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nature Genet. 45: 1055-1060, 2013. [PubMed: 23913004] [Full Text: https://doi.org/10.1038/ng.2716]
Baig, S. M., Koschak, A., Lieb, A., Gebhart, M., Dafinger, C., Nurnberg, G., Ali, A., Ahmad, I., Sinnegger-Brauns, M. J., Brandt, N., Engel, J., Mangoni, M. E., Farooq, M., Khan, H. U., Nurnberg, P., Striessnig, J., Bolz, H. J. Loss of Ca(v)1.3 (CACNA1D) function in a human channelopathy with bradycardia and congenital deafness. Nature Neurosci. 14: 77-84, 2011. [PubMed: 21131953] [Full Text: https://doi.org/10.1038/nn.2694]
Chin, H., Kozak, C. A., Kim, H.-L., Mock, B., McBride, O. W. A brain L-type calcium channel alpha-1 subunit gene (CCHL1A2) maps to mouse chromosome 14 and human chromosome 3. Genomics 11: 914-919, 1991. [PubMed: 1664412] [Full Text: https://doi.org/10.1016/0888-7543(91)90014-6]
Davare, M. A., Avdonin, V., Hall, D. D., Peden, E. M., Burette, A., Weinberg, R. J., Horne, M. C., Hoshi, T., Hell, J. W. A beta-2 adrenergic receptor signaling complex assembled with the Ca(2+) channel Ca(V)1.2. Science 293: 98-101, 2001. Note: Erratum: Science 293: 804 only, 2001. [PubMed: 11441182] [Full Text: https://doi.org/10.1126/science.293.5527.98]
Gross, M. B. Personal Communication. Baltimore, Md. 12/9/2016.
Jinnah, H. A., Yitta, S., Drew, T., Kim, B. S., Visser, J. E., Rothstein, J. D. Calcium channel activation and self-biting in mice. Proc. Nat. Acad. Sci. 96: 15228-15232, 1999. [PubMed: 10611367] [Full Text: https://doi.org/10.1073/pnas.96.26.15228]
Liu, X., Yang, P. S., Yang, W., Yue, D. T. Enzyme-inhibitor-like tuning of Ca(2+) channel connectivity with calmodulin. Nature 463: 968-972, 2010. Note: Erratum: Nature 464: 1390 only, 2010. [PubMed: 20139964] [Full Text: https://doi.org/10.1038/nature08766]
Mori, Y., Friedrich, T., Kim, M.-S., Mikami, A., Nakai, J., Ruth, P., Bosse, E., Hofmann, F., Flockerzi, V., Furuichi, T., Mikoshiba, K., Imoto, K., Tanabe, T., Numa, S. Primary structure and functional expression from complementary DNA of a brain calcium channel. Nature 350: 398-402, 1991. [PubMed: 1849233] [Full Text: https://doi.org/10.1038/350398a0]
Pennartz, C. M. A., de Jeu, M. T. G., Bos, N. P. A., Schaap, J., Geurtsen, A. M. S. Diurnal modulation of pacemaker potentials and calcium current in the mammalian circadian clock. Nature 416: 286-290, 2002. [PubMed: 11875398] [Full Text: https://doi.org/10.1038/nature728]
Platzer, J., Engel, J., Schrott-Fischer, A., Stephan, K., Bova, S., Chen, H., Zheng, H., Striessnig, J. Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca(2+) channels. Cell 102: 89-97, 2000. [PubMed: 10929716] [Full Text: https://doi.org/10.1016/s0092-8674(00)00013-1]
Scholl, U. I., Goh, G., Stolting, G., Campos de Oliveira, R., Choi, M., Overton, J. D., Fonseca, A. L., Korah, R., Starker, L. F., Kunstman, J. W., Prasad, M. L., Hartung, E. A., and 16 others. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nature Genet. 45: 1050-1054, 2013. [PubMed: 23913001] [Full Text: https://doi.org/10.1038/ng.2695]
Seino, S., Chen, L., Seino, M., Blondel, O., Takeda, J., Johnson, J. H., Bell, G. I. Cloning of the alpha-1 subunit of a voltage-dependent calcium channel expressed in pancreatic beta-cells. Proc. Nat. Acad. Sci. 89: 584-588, 1992. [PubMed: 1309948] [Full Text: https://doi.org/10.1073/pnas.89.2.584]
Seino, S., Yamada, Y., Espinosa, R., III, Le Beau, M. M., Bell, G. I. Assignment of the gene encoding the alpha-1 subunit of the neuroendocrine/brain-type calcium channel (CACNL1A2) to human chromosome 3, band p14.3. Genomics 13: 1375-1377, 1992. [PubMed: 1324226] [Full Text: https://doi.org/10.1016/0888-7543(92)90078-7]
Tsien, R. W., Ellinor, P. T., Horne, W. A. Molecular diversity of voltage-dependent Ca(2+) channels. Trends Pharm. Sci. 12: 349-354, 1991. [PubMed: 1659003] [Full Text: https://doi.org/10.1016/0165-6147(91)90595-j]
Williams, M. E., Feldman, D. H., McCue, A. F., Brenner, R., Velicelebi, G., Ellis, S. B., Harpold, M. M. Structure and functional expression of alpha-1, alpha-2, and beta subunits of a novel human neuronal calcium channel subtype. Neuron 8: 71-84, 1992. [PubMed: 1309651] [Full Text: https://doi.org/10.1016/0896-6273(92)90109-q]