Alternative titles; symbols
HGNC Approved Gene Symbol: CACNA1E
Cytogenetic location: 1q25.3 Genomic coordinates (GRCh38): 1:181,317,699-181,808,084 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q25.3 | Developmental and epileptic encephalopathy 69 | 618285 | Autosomal dominant | 3 |
The CACNA1E gene encodes a functionally critical subunit of a high voltage-activated, rapidly inactivating R-type calcium channel which initiates rapid synaptic transmission in the central nervous system (summary by Helbig et al., 2018).
Using mouse Cacn1e as probe, Williams et al. (1994) cloned CACNA1E, which they designated alpha-1E-1, from a hippocampus cDNA library. The deduced 2,251-amino acid protein has a calculated molecular mass of about 255 kD. Williams et al. (1994) also cloned an isoform that has a 19-amino acid repeat sequence. This isoform, which they called alpha-1E-3, contains 2,270 amino acids and has a calculated molecular mass of about 257 kD. There are 24 transmembrane regions, organized into 4 repeats of 6 transmembrane regions, which are characteristic of other Ca(2+) channel alpha-1 subunits. A large cytoplasmic loop exists between transmembrane regions IIS6 and IIIS1. Alpha-1E-1 contains 1 casein kinase II (see 115440) phosphorylation site between transmembrane regions IIS5 and IIS6, and alpha 1E-3 contains 2. Human alpha-1E-3 shares 61% identity with CACNA1A (601011), 60% identity with CACNA1B (601012), and 96.3% identity with mouse alpha-1E. The mammalian alpha-1E sequences share about 67% identity with the marine ray doe-1 sequence. RT-PCR indicated expression in all neuronal tissues tested, as well as in human kidney and mouse retina, spleen, and pancreatic islet cells. Expression was also detected in human neuroblastoma, rat insulinoma, and mouse anterior pituitary cell lines. In situ hybridization of mouse brain slices revealed wide expression.
Williams et al. (1994) showed that expression of CACNA1E in human embryonic kidney cells and Xenopus oocytes produced high voltage-activated Ca(2+) currents that inactivated rapidly. The current size was significantly enhanced by coexpression with neuronal alpha-2/delta (114204) and beta (see 114207) Ca(2+) channel subunits.
Diriong et al. (1995) mapped the CACNL1A6 gene to 1q25-q31 by fluorescence in situ hybridization. Yamazaki et al. (1998) confirmed the mapping to 1q25-q32 by radiation hybrid analysis.
In 30 unrelated patients with developmental and epileptic encephalopathy-69 (DEE69; 618285), Helbig et al. (2018) identified 14 different de novo heterozygous missense mutations in the CACNA1E gene (see, e.g., 601013.0001-601013.0005). The variants, which were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, occurred throughout the gene, although most clustered in the cytoplasmic ends of S6 segment transmembrane domains that line the inner pore of the channel and form the activation gate. All mutations were classified as pathogenic according to ACMG guidelines, and none were found in the ExAC or gnomAD databases. There were several recurrent mutations. In vitro functional expression studies of some of the mutations in human tsA201 transformed kidney cells showed that they resulted in consistent gain-of-function effects, including facilitated voltage-dependent channel activation, slowed inactivation, and increased current density compared to wildtype. The findings indicated that the mutations perturb the gating properties of the channel, resulting in increased inward calcium currents that may affect neuronal excitability and synaptic transmission. Three additional patients (31, 32, and 33) with a milder neurologic phenotype were found to carry heterozygous frameshift or nonsense mutations in the CACNA1E gene that were predicted to result in a loss of function and haploinsufficiency. Functional studies of these variants were not performed. One of these patients inherited the mutation from an apparently unaffected father, another was somatic mosaic for the mutation, and parental DNA from the third was unavailable. Thus, the significance of these loss-of-function mutations was unclear. The patients were ascertained though international collaboration between research and diagnostic sequencing laboratories.
Heyne et al. (2018) analyzed de novo variants in 6,753 parent-offspring trios with variable neurodevelopmental disorders, including epilepsy. They identified 11 individuals with de novo variants, including 9 missense and 2 truncating. One of the 11 variants was present in ExAC, and 4 were associated with epilepsy. The authors noted that further studies with deep phenotyping were needed to characterize the phenotypic spectrum resulting from mutations in CACNA1E.
Royer-Bertrand et al. (2021) described 7 patients, aged 18 months to 31 years, with de novo heterozygous mutations in the CACNA1E gene, including 6 missense and 1 splicing. None of the mutations were found in the gnomAD database. No functional evidence was provided for any of the mutations, but codon 702 appeared to be a hotspot. The only patient (patient 4) who had seizures (infantile spasms) had an ala702-to-ser substitution (601013.0006).
Matsuda et al. (2001) found that Cacna1e-null mice were heavier than wildtype mice. In glucose tolerance and insulin tolerance tests, mutant mice showed a significantly higher blood glucose level. However, stress-induced blood glucose changes were similar to wildtype mice.
In Cacna1e-null mice, Jing et al. (2005) observed a 20% reduction in glucose-evoked insulin secretion. Dynamic insulin release measurements demonstrated that genetic or pharmacologic Cacna1e ablation strongly suppressed second-phase secretion, whereas first-phase secretion was unaffected, both in vitro and in vivo. Suppression of the second phase coincided with an 18% reduction in oscillatory Ca(2+) signaling and a 25% reduction in hormone-containing granule recruitment after completion of the initial exocytotic burst in individual null beta cells. Jing et al. (2005) proposed that CACNA1E channels have a specific role in second-phase insulin release by mediating the Ca(2+) entry needed for replenishment of the releasable pool of granules.
In a 4-year-old girl (patient 14) with lethal developmental and epileptic encephalopathy-69 (DEE69; 618285), Helbig et al. (2018) identified a de novo heterozygous c.2093T-C transition (c.2093T-C, NM_000721.3) in the CACNA1E gene, resulting in a phe698-to-ser (F698S) substitution in the cytoplasmic end of the S6 transmembrane segment of domain II. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases. In vitro functional expression studies showed that the mutation resulted in a gain-of-function effect with increased channel activation compared to wildtype. The patient had onset of infantile spasms at 1 week of age. EEG showed multifocal discharges and hypsarrhythmia.
In 3 unrelated patients (patients 16, 17, and 18) with developmental and epileptic encephalopathy-69 (DEE69; 618285), Helbig et al. (2018) identified a de novo heterozygous c.2101A-G transition (c.2101A-G, NM_000721.3) in the CACNA1E gene, resulting in an ile701-to-val (I701V) substitution in the cytoplasmic end of the S6 transmembrane segment of domain II. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases. In vitro functional expression studies showed that the mutation resulted in a gain-of-function effect with increased channel activation compared to wildtype. The patients had onset of seizures between 5 and 9 months of age. EEG showed multifocal discharges.
In 6 unrelated patients (patients 19-24) with developmental and epileptic encephalopathy-69 (DEE69; 618285), Helbig et al. (2018) identified a de novo heterozygous c.2104G-A transition (c.2104G-A, NM_000721.3) in the CACNA1E gene, resulting in an ala702-to-thr (A702T) substitution in the cytoplasmic end of the S6 transmembrane segment of domain II. The mutation, which was found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases. In vitro functional expression studies showed that the mutation resulted in a gain-of-function effect with increased channel activation compared to wildtype. The patients had onset of various types of seizures between 3 and 6 months of age. EEG showed multifocal discharges and hypsarrhythmia.
In a 1.5-year-old boy (patient 12) with developmental and epileptic encephalopathy-69 (DEE69; 618285), Helbig et al. (2018) identified a de novo heterozygous c.1807A-C transversion (c.1807A-C, NM_000721.3) in the CACNA1E gene, resulting in an ile603-to-leu (I603L) substitution in the domain II S4-S5 linker domain. The mutation, which was found by panel-based next-generation gene sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases. In vitro functional expression studies showed that the mutation resulted in a massive increase in whole-cell current density with a hyperpolarizing shift in half-activation voltage compared to wildtype. The patient had onset of focal motor seizures at 7 months of age. EEG showed multifocal discharges.
In 9 unrelated patients (patients 3-11) with developmental and epileptic encephalopathy-69 (DEE69; 618285), Helbig et al. (2018) identified a de novo heterozygous c.1054G-A transition (c.1054G-A, NM_000721.3) in the CACNA1E gene, resulting in a gly352-to-arg (G352R) substitution in the cytoplasmic end of the S6 transmembrane segment of domain I. The mutation, which was found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases. Functional expression studies of the variant were not performed. The patients had onset of various types of seizures between 2 months and 3 years of age.
In a 31-year-old female with severe intellectual disability and onset of infantile spasms at age 6 months (DEE69; 618285), Royer-Bertrand et al. (2021) identified a de novo heterozygous c.2014C-T transition (c.2014C-T, NM_00721.4) in the CACNA1E gene, resulting in an ala702-to-ser substitution. The variant was not present in the gnomAD database.
Diriong, S., Lory, P., Williams, M. E., Ellis, S. B., Harpold, M. M., Taviaux, S. Chromosomal localization of the human genes for alpha-1A, alpha-1B, and alpha-1E voltage-dependent Ca(2+) channel subunits. Genomics 30: 605-609, 1995. [PubMed: 8825650] [Full Text: https://doi.org/10.1006/geno.1995.1284]
Helbig, K. L., Lauerer, R. J., Bahr, J. C., Souza, I. A., Myers, C. T., Uysal, B., Schwarz, N., Gandini, M. A., Huang, S., Keren, B., Mignot, C., Afenjar, A., and 90 others. De novo pathogenic variants in CACNA1E cause developmental and epileptic encephalopathy with contractures, macrocephaly, and dyskinesias. Am. J. Hum. Genet. 103: 666-678, 2018. Note: Erratum: Am. J. Hum. Genet. 104: 562 only, 2019. [PubMed: 30343943] [Full Text: https://doi.org/10.1016/j.ajhg.2018.09.006]
Heyne, H. O., Singh, T., Stamberger, H., Abou Jamra, R., Caglayan, H., Craiu, D., De Jonghe, P., Guerrini, R., Helbig, K. L., Koeleman, B. P. C., Kosmicki, J. A., Linnankivi, T., and 18 others. De novo variants in neurodevelopmental disorders with epilepsy. Nature Genet. 50: 1048-1053, 2018. [PubMed: 29942082] [Full Text: https://doi.org/10.1038/s41588-018-0143-7]
Jing, X., Li, D.-Q., Olofsson, C. S., Salehi, A., Surve, V. V., Caballero, J., Ivarsson, R., Lundquist, I., Pereverzev, A., Schneider, T., Rorsman, P., Renstrom, E. Cav2.3 calcium channels control second-phase insulin release. J. Clin. Invest. 115: 146-154, 2005. [PubMed: 15630454] [Full Text: https://doi.org/10.1172/JCI22518]
Matsuda, Y., Saegusa, H., Zong, S., Noda, T., Tanabe, T. Mice lacking Ca(V)2.3(alpha-1E) calcium channel exhibit hyperglycemia. Biochem. Biophys. Res. Commun. 289: 791-795, 2001. [PubMed: 11735114] [Full Text: https://doi.org/10.1006/bbrc.2001.6051]
Royer-Bertrand, B., Jequier Gygax, M., Cisarova, K., Rosenfeld, J. A., Bassetti, J. A., Moldovan, O., O'Heir, E., Burrage, L. C., Allen, J., Emrick, L. T., Eastman, E., Kumps, C., and 12 others. De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures. Molec. Autism 12: 69, 2021. [PubMed: 34702355] [Full Text: https://doi.org/10.1186/s13229-021-00473-3]
Williams, M. E., Marubio, L. M., Deal, C. R., Hans, M., Brust, P. F., Philipson, L. H., Miller, R. J., Johnson, E. C., Harpold, M. M., Ellis, S. B. Structure and functional characterization of neuronal alpha-1E calcium channel subtypes. J. Biol. Chem. 269: 22347-22357, 1994. [PubMed: 8071363]
Yamazaki, K., Oki, T., Tanaka, I. Locations of human genes for alpha(1A), alpha(1B), and alpha(1E) calcium channels determined by radiation hybrid mapping. J. Hered. 89: 269-271, 1998. [PubMed: 9656471] [Full Text: https://doi.org/10.1093/jhered/89.3.269]