HGNC Approved Gene Symbol: CACNB4
SNOMEDCT: 718756005;
Cytogenetic location: 2q23.3 Genomic coordinates (GRCh38) : 2:151,832,771-152,099,167 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q23.3 | ?Episodic ataxia, type 5 | 613855 | Autosomal dominant | 3 |
| {Epilepsy, idiopathic generalized, susceptibility to, 9} | 607682 | Autosomal dominant | 3 | |
| {Epilepsy, juvenile myoclonic, susceptibility to, 6} | 607682 | Autosomal dominant | 3 |
By amplification of human cerebellar RNA using primer pairs complementary to the rat beta-4 cDNA, followed by database searching with a rat Cacnb4 cDNA sequence, Escayg et al. (1998) identified the full-length human CACNB4 sequence. The 1,560-bp open reading frame predicts a 58-kD, 520-amino acid protein that is 99% identical to the rat protein. Northern blot analysis of human cerebellar RNA demonstrated 1 major 9-kb CACNB4 transcript. RT-PCR of total RNA detected expression in cerebellum, kidney, testis, retina, lymphoblasts, and circulating lymphocytes. In situ hybridization to mouse retina sections localized Cacnb4 expression to the ganglion cell and inner nuclear layers.
Lory et al. (1997) suggested a unified nomenclature for voltage-gated calcium channel genes.
Escayg et al. (1998) determined that the CACNB4 gene contains 13 coding exons distributed over more than 55 kb of genomic DNA.
Taviaux et al. (1997) used a cDNA probe covering the 3-prime end of the human beta-4 gene (see GenBank U95020) to map the gene encoding the beta-4 isoform of the regulatory beta subunit of voltage-activated Ca(2+) channels, CACNB4, to 2q22-q23 by fluorescence in situ hybridization. CACNB4 is a member of the voltage-gated calcium channel gene superfamily; see also CACNB1 (114207). Betz et al. (1998) likewise mapped the CACNB4 gene to 2q22-q23. They first screened a panel of somatic cell hybrids by PCR and sublocalized the gene by study of a panel of radiation hybrids.
To elucidate the molecular mechanism of the interaction between calcium channel alpha-1 (see 601011) and beta subunits, Chen et al. (2004) determined the crystal structures of the conserved core region of beta-3 (CACNB3; 601958), alone and in complex with the alpha-interaction domain (AID), and of beta-4 (CACNB4) alone. The structures showed that the beta subunit core contains 2 interacting domains: a Src homology-3 (SH3) domain and a guanylate kinase domain. The AID binds to a hydrophobic groove in the guanylate kinase domain through extensive interactions, conferring extremely high affinity between alpha-1 and beta subunits. The beta-interaction domain (BID) is essential both for the structural integrity of and for bridging the SH3 and guanylate kinase domains, but it does not participate directly in binding alpha-1.
Inactivation of the Cacnb4 gene in the mouse neurologic mutant 'lethargic' results in a complex neurologic disorder that includes absence epilepsy and ataxia. To determine the role of this gene in related human disorders, Escayg et al. (2000) screened for mutations in small pedigrees with familial epilepsy and ataxia. A premature-termination mutation, arg482 to ter (R482X; 601949.0001), was identified in a patient with juvenile myoclonic epilepsy (EJM6; see 607682). The R482X protein lacks the 38 C-terminal amino acids containing part of an interaction domain for the alpha-1 subunit. A cys104-to-phe (C104F; 601949.0002) mutation was identified both in a German family with idiopathic generalized epilepsy and praxis-induced seizures (EIG9; 607682), and in a French Canadian family with episodic ataxia type 5 (EA5; 613855). The results of functional tests of the truncated protein R482X in Xenopus laevis oocytes demonstrated a small decrease in the fast time constant for inactivation of the cotransfected alpha-1 subunit. Escayg et al. (2000) also described 2 noncoding single-nucleotide substitutions that are present at polymorphic frequency, and a previously unrecognized first intron of CACNB4 that interrupts exon 1 at codon 21. The total number of families screened was 161: 90 families with idiopathic generalized epilepsy and 71 families with episodic ataxia. The families with epilepsy included 19 families with childhood absence epilepsy, 22 with juvenile absence epilepsy, and 49 with juvenile myoclonic epilepsy.
The mouse neurologic mutation 'lethargic' arose spontaneously in the mouse inbred strain BALB/cGn in 1962. Homozygotes are recognizable at 15 days of age by ataxia and lethargic behavior followed within a few days by the onset of spontaneous focal motor seizures. A second seizure type, consisting of brief episodes of behavioral immobility, is accompanied by generalized cortical spike-wave discharges. Electrophysiologically and pharmacologically, these seizures resemble the absence seizures of human petit mal epilepsy and those seen in the 'tottering' mouse (see CACNA1A, 601011). No pathologic changes have been observed in the brain, spinal cord, or muscles of affected lethargic mice. Ca(2+) channel beta subunits regulate voltage-dependent calcium currents through direct interaction with alpha-1 (see 601011) subunits. The beta- and alpha-1-binding motifs are conserved, and all beta subunits can stimulate current amplitude, voltage dependence, and kinetics when coexpressed with various alpha-1 subunits. Burgess et al. (1997) used a positional candidate approach to determine that the ataxia and seizures in the lethargic (lh) mouse arise from mutations in the beta-subunit gene (Cchb4) on mouse chromosome 2. A 4-nucleotide insertion into a splice donor site resulted in exon skipping, translational frameshift, and protein truncation with loss of the alpha-1-binding site. The lethargic phenotype was the first example of a mammalian neurologic disease caused by an inherited defect of a nonpore-forming subunit of a voltage-gated ion channel.
By knockin analysis in cultured rat muscle cells and neurons, Coste de Bagneaux et al. (2020) showed that a homozygous leu125 to pro (L125P) mutation in the beta-4b splice variant of the calcium channel Cacnb4 impaired its association with calcium channel complexes and its nuclear targeting. The L125P mutation did not abrogate complex formation of beta-4b with Ppp2r5d (601646), a regulatory subunit of protein phosphatase 2A that contributes to nuclear localization of beta-4b, but it disrupted the interaction with Tnik (610005). Moreover, the L125P mutation did not abolish the augmentation of calcium currents by beta-4b, but it prevented the formation of a stable complex between beta-4b and Cacna1a (601011), the alpha-1 calcium channel subunit.
The report by Badou et al. (2005) on the requirement of CACNB4 for T-lymphocyte functions was retracted.
Escayg et al. (2000) found an arg482-to-ter (R482X) mutation of the CACNB4 gene in a woman who, beginning at age 9 years, had experienced sporadic typical absences (brief spells of loss of consciousness) and repetitive bilateral myoclonic jerks in the shoulders and arms after awakening, without loss of consciousness. Her epilepsy syndrome was classified as juvenile myoclonic epilepsy (EJM6; see 607682). She later experienced several generalized tonic-clonic seizures, usually within 1 hour of awakening. EEGs of the proband's daughter showed generalized 3/s spike-wave discharges without epileptic seizures.
Escayg et al. (2000) found a cys104-to-phe (C104F) missense mutation in affected members of a German family with generalized epilepsy (EIG9; 607682) and praxis-induced seizures, and in a French Canadian family with episodic ataxia type 5 (EA5; 613855). The German family had affected father and son; the French Canadian family had 5 affected individuals in 3 generations. In the German family, the affected father and son presented with an atypical but similar clinical syndrome of idiopathic generalized epilepsy with rare juvenile atypical prolonged absences and occasional generalized tonic-clonic seizures (GTCS). The proband had normal intellectual and psychomotor development. One febrile convulsion occurred at age 3 years. After age 6, he had occasional GTCS, predominantly on awakening, and, after age 12, occasional episodes of absence were described. A prolonged atypical absence occurred in the eldest son at age 14 years, while he was playing cards. At age 17, he experienced GTCS shortly after awakening. Two years later, he experienced a generalized tonic seizure while playing a complex strategic game after sleep withdrawal. He experienced occasional prolonged staring spells when lacking sleep. Both affected individuals reported that seizures were precipitated by playing complex strategic games (praxis induction), suggesting an unusual cognitive trigger of seizure initiation (Inoue et al., 1992). In the French Canadian family with the C104F mutation, the proband, after age 20 years, experienced recurrent episodes of vertigo and ataxia that lasted for several hours. Interictal examination showed spontaneous downbeat and gaze-evoked nystagmus and mild dysarthria and truncal ataxia. The proband's mother had identical episodes of vertigo and ataxia after age 30 years as well as longstanding dysarthria and imbalance. Acetazolamide prevented the attacks in both the proband and the mother, and the attacks recurred when acetazolamide was briefly discontinued.
Badou, A., Basavappa, S., Desai, R., Peng, Y.-Q., Matza, D., Mehal, W. Z., Kaczmarek, L. K., Boulpaep, E. L., Flavell, R. A. Requirement of voltage-gated calcium channel beta-4 subunit for T lymphocyte functions. Science 307: 117-121, 2005. Note: Retraction: Science 310: 1903 only, 2005. [PubMed: 15637280] [Full Text: https://doi.org/10.1126/science.1100582]
Betz, R., Leibiger, B., Farnebo, F., Lagercrantz, S., Piehl, F., Leibiger, I., Larsson, C. Mapping of the human Ca(2+) channel beta-4 subunit to 2q22-23 and its expression in developing mouse. Mammalian Genome 9: 310-311, 1998. [PubMed: 9530629] [Full Text: https://doi.org/10.1007/s003359900755]
Burgess, D. L., Jones, J. M., Meisler, M. H., Noebels, J. L. Mutation of the Ca(2+) channel beta subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse. Cell 88: 385-392, 1997. [PubMed: 9039265] [Full Text: https://doi.org/10.1016/s0092-8674(00)81877-2]
Chen, Y., Li, M., Zhang, Y., He, L., Yamada, Y., Fitzmaurice, A., Shen, Y., Zhang, H., Tong, L., Yang, J. Structural basis of the alpha-1-beta subunit interaction of voltage-gated Ca(2+) channels. Nature 429: 675-680, 2004. [PubMed: 15170217] [Full Text: https://doi.org/10.1038/nature02641]
Coste de Bagneaux, P., von Elsner, L., Bierhals, T., Campiglio, M., Johannsen, J., Obermair, G. J., Hempel, M., Flucher, B. E., Kutsche, K. A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions. PLoS Genet. 16: e1008625, 2020. [PubMed: 32176688] [Full Text: https://doi.org/10.1371/journal.pgen.1008625]
Escayg, A., De Waard, M., Lee, D. D., Bichet, D., Wolf, P., Mayer, T., Johnston, J., Baloh, R., Sander, T., Meisler, M. H. Coding and noncoding variation of the human calcium-channel beta(4)-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am. J. Hum. Genet. 66: 1531-1539, 2000. [PubMed: 10762541] [Full Text: https://doi.org/10.1086/302909]
Escayg, A., Jones, J. M., Kearney, J. A., Hitchcock, P. F., Meisler, M. H. Calcium channel beta-4 (CACNB4): human ortholog of the mouse epilepsy gene lethargic. Genomics 50: 14-22, 1998. [PubMed: 9628818] [Full Text: https://doi.org/10.1006/geno.1998.5311]
Inoue, Y., Suzuki, S., Watanabe, Y., Yagi, K., Seino, M. Non-lesional reflex epilepsy evoked by non-verbal higher cerebral activities. J. Jpn. Epilepsy Soc. 10: 1-9, 1992.
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]
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]