Alternative titles; symbols
HGNC Approved Gene Symbol: CACNB2
Cytogenetic location: 10p12.33-p12.31 Genomic coordinates (GRCh38): 10:18,140,424-18,543,557 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10p12.33-p12.31 | Brugada syndrome 4 | 611876 | Autosomal dominant | 3 |
Williams et al. (1992) isolated a cDNA corresponding to the beta-2 subunit of a voltage-dependent calcium channel from a human hippocampus cDNA library. The deduced 478-amino acid protein has a calculated molecular mass of 53 kD. There was evidence for various tissue-specific transcripts in brain, skeletal muscle, and aorta.
Lambert-Eaton myasthenic syndrome is a paraneoplastic neuromuscular disorder in which an autoimmune response directed against a small-cell lung tumor crossreacts with antigens in the neuromuscular junction. To isolate and characterize the antigens, Rosenfeld et al. (1993) screened a human fetal brain expression library with a high-titer serum from a patient with Lambert-Eaton myasthenic syndrome. The screening resulted in the isolation of a cDNA clone encoding an antigen that they called myasthenic antigen B (MYSB). Of 7 Lambert-Eaton myasthenic syndrome sera, 3 recognized the MYSB fusion protein, whereas none of 34 control sera did. The predicted amino acid sequence of this clone shows a high degree of homology to the beta-subunit of calcium channel complexes.
By PCR using primers based on the sequence of rat brain Cacnb2 and the sequence of the Lambert-Eaton myasthenic syndrome antigen, Allen and Mikala (1998) cloned a splice variant of CACNB2 from human cardiac mRNA that they called beta-2c. The deduced protein contains 660 amino acids.
Yamaguchi et al. (2000) cloned an alternatively spliced CACNB2 variant from human heart RNA that they called beta-2a. The deduced protein contains the N-terminal palmitoylation site found in other mammalian beta-2 isoforms, but it has a shorter N-terminal domain than rabbit beta-2b and human beta-2c.
Taviaux et al. (1997) used a human beta-2 cDNA probe to map the gene encoding the beta-2 isoform of the regulatory beta subunit of voltage-activated Ca(2+) channels, CACNB2, to chromosome 10p12 by fluorescence in situ hybridization. The gene encoding the beta-2 protein, first described as a Lambert-Eaton myasthenic syndrome antigen B in humans, is found close to a region that undergoes chromosome rearrangements in small cell lung cancer with which Lambert-Eaton syndrome has been observed.
By studies in Xenopus oocytes, Williams et al. (1992) found that the beta-2 subunit formed a dihydropyrimidine (DHP)-sensitive, high voltage-activated, long-lasting calcium channel when coexpressed with an alpha-1D (CACNA1D; 114206) subunit. Channel activity was enhanced by coexpression of an alpha-2 (CACNA2D1; 114204) subunit. The beta-2 subunit served an obligatory function in channel activity.
Allen and Mikala (1998) found that expression of the beta-2c isoform of CACNB2 in Xenopus oocytes gave rise to channels that functioned similarly to those containing the beta-1b subunit (CACNB1; 114207) when coexpressed with the alpha-1c (CACNA1C; 114205) and alpha-2/delta-a (CACNA2D1) subunits.
By expression studies in Xenopus oocytes, Yamaguchi et al. (2000) showed that beta-2a and alpha-2/delta cooperatively increased membrane expression of the alpha-1c subunit, whereas their effects on voltage-dependence of the channel complex were additive. Furthermore, the beta-2a subunit, but not the alpha-2/delta subunit, enhanced channel opening.
Viard et al. (2004) found that both mammalian phosphatidylinositol 3-kinase (PI3K)-alpha (see PIK3CA; 171834) and PI3K-gamma (see PIK3CG; 601232) increased the expression of functional Ca(V) channels at the plasma membrane of transfected COS-7 cells. This regulation occurred for channels associated specifically with CACNB2. PI3K-induced regulation was mediated by PI(3,4,5)P3-activated AKT (see 164730) and required the phosphorylation of CACNB2 on a unique serine residue (ser574 in human). In primary cultures of rat dorsal root ganglion cells, acute stimulation of PI3K by tyrosine kinase-associated receptors also induced the translocation of Ca(V) channels to the plasma membrane. Viard et al. (2004) concluded that PI3K-induced regulation of Ca(V) channel trafficking may be a general mechanism for the regulation of calcium entry in excitable cells.
McGee et al. (2004) noted that the C1 and C2 regions of beta subunits share limited sequence homology with the Src (190090) homology-3 (SH3)-guanylate kinase (GK) module that mediates protein-protein interactions in membrane-associated guanylate kinases (MAGUKs; see 305360). They found that mutations that disrupted the assembly of the SH3 fold in rat beta-2a interfered with modulation of the voltage-gated calcium channel by this beta subunit. McGee et al. (2004) showed that a functional beta subunit required intramolecular or intermolecular SH3-GK assembly. They concluded that the SH3-GK module transduces regulation of channel activity by beta subunits.
Crystal Structure
Van Petegem et al. (2004) reported the high resolution crystal structure of the CAVB2A conserved core, alone and in complex with the alpha-interaction domain. The structure shows that CAVB2A engages the alpha-interaction domain through an extensive, conserved hydrophobic cleft, which Van Petegem et al. (2004) named the alpha-binding pocket (ABP). The ABP-alpha-interaction domain interaction positions one end of the CAVB near the intracellular end of a pore-lining segment that has a critical role in voltage-gated calcium channel interaction.
Antzelevitch et al. (2007) screened 82 consecutive probands with a clinical diagnosis of Brugada syndrome (see Brugada syndrome-1; 601144) for mutations in 16 ion channel genes. In 1 Brugada proband who exhibited a shortened QTc interval of 330 ms (see Brugada syndrome-4; BRGDA4, 611876), they identified a heterozygous missense mutation in the CACNB2 gene (S481L; 600003.0001).
In a 34-year-old man with Brugada syndrome, Cordeiro et al. (2009) screened for mutations in 15 ion channel genes and identified only 1 heterozygous missense mutation in the CACNB2 gene (T11I; 600003.0002).
Crotti et al. (2012) analyzed 12 Brugada syndrome susceptibility genes in 129 unrelated patients with possible or probable Brugada syndrome and identified SCN5A (600163) mutations in 21 (16.3%) of the patients; only 6 (4.6%) of the patients carried a mutation in 1 of the other 11 genes, including 2 asymptomatic patients with a type 1 Brugada syndrome ECG pattern who were each heterozygous for a putative pathogenic missense mutation in the CACNB2 gene (V340I and E499D, respectively).
CACNB2 is a member of the voltage-gated calcium channel gene superfamily. Lory et al. (1997) provided a unified nomenclature for voltage-gated calcium channel genes.
In 6 affected members of a family with Brugada syndrome and a shortened QTc interval (Brugada syndrome-4; 611876), Antzelevitch et al. (2007) identified heterozygosity for a 1442C-T transition in exon 13 of the CACNB2 gene, predicted to result in a ser481-to-leu (S481L) substitution downstream of the beta-subunit interaction domain segment. The mutation was not found in 4 unaffected family members or in 400 ethnically matched control alleles. Patch-clamp experiments in Chinese hamster ovary (CHO) cells demonstrated a marked reduction in current amplitude of mutant channels compared to wildtype, although voltage at peak current was unchanged; confocal microscopy revealed normal trafficking of channels containing S481L subunits.
In a 34-year-old man with Brugada syndrome-4 (BRGDA4; 611876), Cordeiro et al. (2009) identified a heterozygous C-to-T transition in exon 1 of the CACNB2b gene, resulting in a thr11-to-ile (T11I) substitution. The mutation was not present in 214 ethnically matched control alleles. The mutation occurred upstream of the beta-subunit interaction domain segment in variable domain 1 near the N terminus. Patch-clamp experiments in TSA201 cells showed no significant difference between wildtype and T11I in peak calcium current density, steady- state inactivation, or recovery from inactivation; however, both fast and slow decays of peak calcium channel were significantly faster in mutant channels between 0 and 20 mV. Action potential voltage clamp experiments showed that total charge was reduced by almost half compared to wildtype. The findings suggested that accelerated inactivation of the channel results in a loss of function.
Allen, T. J. A., Mikala, G. Effects of temperature on human L-type cardiac Ca(2+) channels expressed in Xenopus oocytes. Pflugers Arch. 436: 238-247, 1998. [PubMed: 9594024] [Full Text: https://doi.org/10.1007/s004240050628]
Antzelevitch, C., Pollevick, G. D., Cordeiro, J. M., Casis, O., Sanguinetti, M. C., Aizawa, Y., Guerchicoff, A., Pfeiffer, R., Oliva, A., Wollnik, B., Gelber, P., Bonaros, E. P., Jr., and 11 others. 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: 442-449, 2007. [PubMed: 17224476] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.106.668392]
Cordeiro, J. M., Marieb, M., Pfeiffer, R., Calloe, K., Burashnikov, E., Antzelevitch, C. Accelerated inactivation of the L-type calcium current due to a mutation in CACNB2b underlies Brugada syndrome. J. Molec. Cell. Cardiol. 46: 695-703, 2009. [PubMed: 19358333] [Full Text: https://doi.org/10.1016/j.yjmcc.2009.01.014]
Crotti, L., Marcou, C. A., Tester, D. J., Castelletti, S., Giudicessi, J. R., Torchio, M., Medeiros-Domingo, A., Simone, S., Will, M. L., Dagradi, F., Schwartz, P. J., Ackerman, M. J. Spectrum and prevalence of mutations involving BrS1- through BrS12-susceptibility genes in a cohort of unrelated patients referred for Brugada syndrome genetic testing: implications for genetic testing. J. Am. Coll. Cardiol. 60: 1410-1418, 2012. [PubMed: 22840528] [Full Text: https://doi.org/10.1016/j.jacc.2012.04.037]
Lory, P., Ophoff, R. A., Nahmias, J. Towards a unified nomenclature describing voltage-gated calcium channel genes. Hum. Genet. 100: 149-150, 1997. [PubMed: 9254840] [Full Text: https://doi.org/10.1007/s004390050481]
McGee, A. W., Nunziato, D. A., Maltez, J. M., Prehoda, K. E., Pitt, G. S., Bredt, D. S. Calcium channel function regulated by the SH3-GK module in beta subunits. Neuron 42: 89-99, 2004. [PubMed: 15066267] [Full Text: https://doi.org/10.1016/s0896-6273(04)00149-7]
Rosenfeld, M. R., Wong, E., Dalmau, J., Manley, G., Posner, J. B., Sher, E., Furneaux, H. M. Cloning and characterization of a Lambert-Eaton myasthenic syndrome antigen. Ann. Neurol. 33: 113-120, 1993. [PubMed: 8494331] [Full Text: https://doi.org/10.1002/ana.410330126]
Taviaux, S., Williams, M. E., Harpold, M. M., Nargeot, J., Lory, P. Assignment of human genes for beta-2 and beta-4 subunits of voltage-dependent Ca(2+) channels to chromosomes 10p12 and 2q22-q23. Hum. Genet. 100: 151-154, 1997. [PubMed: 9254841] [Full Text: https://doi.org/10.1007/pl00008704]
Van Petegem, F., Clark, K. A., Chatelain, F. C., Minor, D. L., Jr. Structure of a complex between a voltage-gated calcium channel beta-subunit and an alpha-subunit domain. Nature 429: 671-675, 2004. [PubMed: 15141227] [Full Text: https://doi.org/10.1038/nature02588]
Viard, P., Butcher, A. J., Halet, G., Davies, A., Nurnberg, B., Heblich, F., Dolphin, A. C. PI3K promotes voltage-dependent calcium channel trafficking to the plasma membrane. Nature Neurosci. 7: 939-946, 2004. [PubMed: 15311280] [Full Text: https://doi.org/10.1038/nn1300]
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]
Yamaguchi, H., Okuda, M., Mikala, G., Fukasawa, K., Varadi, G. Cloning of the beta-2a subunit of the voltage-dependent calcium channel from human heart: cooperative effect of alpha-2/delta and beta-2a on the membrane expression of the alpha-1c subunit. Biochem. Biophys. Res. Commun. 267: 156-163, 2000. [PubMed: 10623591] [Full Text: https://doi.org/10.1006/bbrc.1999.1926]