HGNC Approved Gene Symbol: CACNA1G
SNOMEDCT: 1208513005;
Cytogenetic location: 17q21.33 Genomic coordinates (GRCh38): 17:50,560,715-50,627,474 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.33 | Spinocerebellar ataxia 42 | 616795 | Autosomal dominant | 3 |
| Spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits | 618087 | Autosomal dominant | 3 |
The CACNA1G gene encodes the low-voltage-activated Ca(v)3.1 T-type calcium channel. CACNA1G is highly expressed in Purkinje neurons and deep cerebellar nuclei (summary by Chemin et al., 2018).
Low-voltage-activated calcium channels are referred to as 'T' type because their currents are both transient, owing to fast inactivation, and tiny, owing to small conductance. T-type channels are thought to be involved in pacemaker activity, low-threshold calcium spikes, neuronal oscillations and resonance, and rebound burst firing (summary by Perez-Reyes et al., 1998).
By searching an EST database for sequences related to calcium channels, Perez-Reyes et al. (1998) identified a partial human cDNA encoding a novel channel that they designated alpha-1G or Ca(V)T.1. The authors used the partial cDNA to isolate additional human, rat, and mouse alpha-1G cDNAs. Northern blot analysis of human and rat tissues indicated that the alpha-1G gene was expressed as an 8.5-kb mRNA predominantly in brain. An additional 9.7-kb transcript was also detected. When expressed in Xenopus oocytes, the rat alpha-1G channel exhibited the properties of a low-voltage-activated T-type calcium channel.
Jagannathan et al. (2002) found that multiple isoforms of CACNA1G and at least 2 isoforms of CACNA1H (607904) are generated by alternative splicing and are expressed in testis. In situ hybridization localized transcripts both in germ cells and in other testis cell types. Within cardiac tissue, both CACNA1G and CACNA1H were expressed in vascular tissue and not in myocytes.
The CACNA1G gene is highly expressed in Purkinje cells and deep cerebellar nuclei neurons of the cerebellum (summary by Coutelier et al., 2015).
By whole-cell patch-clamp studies, Jagannathan et al. (2002) detected T-type voltage-operated Ca(2+) channel currents in isolated round spermatids. Currents were consistent with those generated by CACNA1H or CACNA1G channels.
By action potential clamp studies, Chemin et al. (2002) found significant differences in the biochemical properties of CACNA1G, CACNA1H, and CACNA1I (608230) following transient transfection in human embryonic kidney cells. Using firing activities recorded in dissociated rat cerebellar Purkinje neurons and thalamocortical relay neurons as voltage-clamp waveforms, they showed that CACNA1I currents contributed to sustained electrical activities, while CACNA1G and CACNA1H currents generated short burst firing. Chemin et al. (2002) hypothesized that each of the T-channel pore-forming subunits displays specific gating properties that uniquely contribute to neuronal firing and that CACNA1I channels provide pacemaker activity.
By FISH and radiation hybrid analysis, Perez-Reyes et al. (1998) mapped the CACNA1G gene to 17q22. Using interspecific backcross analysis, they mapped the mouse Cacna1g gene to the distal portion of chromosome 11, in a region showing homology of synteny with 17q22.
Spinocerebellar Ataxia 42
In affected members of 3 unrelated French families with spinocerebellar ataxia-42 (SCA42; 616795), Coutelier et al. (2015) identified a heterozygous missense mutation in the CACNA1G gene (R1715H; 605065.0001). The mutation in the first family was found by linkage analysis combined with whole-exome sequencing; the mutation in the other 2 families was found by screening of a large number of probands with a similar disorder. The mutation segregated with the phenotype in all families, and haplotype analysis excluded a founder effect. The substitution occurred in the voltage-sensing region. In vitro electrophysiologic studies and computer modeling simulations suggested that the mutation resulted in decreased neuronal excitability.
Morino et al. (2015) identified heterozygosity for the same R1715H mutation in the CACNA1G gene in affected members of 2 unrelated Japanese families with SCA42. The mutations were found by linkage analysis and exome sequencing and confirmed by Sanger sequencing. The mutation segregated with the disorder in both families, which shared a haplotype containing the mutation. Electrophysiologic studies showed that the mutation shifted the activation to more positive (depolarized) membrane potentials. Inactivation potentials were also shifted to more positive membrane potentials, although the slope factor was not significantly different. The findings indicated that SCA42 is a channelopathy.
Spinocerebellar Ataxia 42, Early-Onset, Severe, with Neurodevelopmental Deficits
In 4 unrelated girls with early-onset severe spinocerebellar ataxia-42 with neurodevelopmental deficits (SCA42ND; 618087), Chemin et al. (2018) identified de novo heterozygous missense mutations in the CACNA1G gene (A961T, 605065.0002 and M1531V, 605065.0003). Three patients carried the A961T variant, suggesting a mutation hotspot. The mutation in the first patient was found by whole-exome sequencing and confirmed by Sanger sequencing. The other patients were identified through collaborative data sharing of patients with a similar phenotype who underwent exome sequencing. Electrophysiologic studies in HEK293 cells showed that the mutant currents activated at more negative potentials and had markedly slowed inactivation kinetics compared to wildtype. This resulted in increased calcium influx, consistent with a gain of function. Computational modeling of the mutations confirmed that the mutations would promote increased firing activity in deep cerebellar neurons. These currents were blocked in vitro in the presence of TTA-P2, a selective T-type calcium channel blocker.
To investigate whether T-type Ca(2+) channels in thalamocortical relay (TC) neurons are involved in the generation of spike-and-wave discharges (SWDs), Kim et al. (2001) used gene targeting to generate a null mutation of CACNA1G that encodes the pore-forming subunit of T-type Ca(2+) channels. The knockout mice grew normally and were fertile. General development of the brain and major organs appeared normal. Using pharmacologic models, Kim et al. (2001) analyzed the ability of mutant mice to generate SWDs. The thalamocortical relay neurons of the knockout mice lacked the burst mode firing of action potentials, whereas they showed the normal pattern of tonic mode firing. The knockout thalamus was specifically resistant to the generation of SWDs in response to GABA-B receptor (see 603540) activation. Kim et al. (2001) concluded that the modulation of the intrinsic firing pattern mediated by CACNA1G T-type Ca(2+) channels plays a critical role in the generation of GABA-B receptor-mediated SWDs in the thalamocortical pathway, the hallmark of absence seizures.
Sensations from viscera, like fullness, easily become painful if the stimulus persists. Kim et al. (2003) demonstrated that mice lacking alpha 1G T-type calcium channels show hyperalgesia to visceral pain. Thalamic infusion of a T-type blocker induced similar hyperalgesia in wildtype mice. In response to visceral pain, the ventroposterolateral thalamic neurons evoked a surge of single spikes, which then slowly decayed as T type-dependent burst spikes gradually increased. In alpha-1G-deficient neurons, the single-spike response persisted without burst spikes. Kim et al. (2003) concluded that T-type calcium channels underlie an antinociceptive mechanism operating in the thalamus and that their findings support the idea that burst firing plays a critical role in sensory gating in the thalamus.
In affected members of 3 unrelated French families with spinocerebellar ataxia-42 (SCA42; 616795), Coutelier et al. (2015) identified a heterozygous c.5144G-A transition (c.5144G-A, NM_018896.4) in the CACNA1G gene, resulting in an arg1715-to-his (R1715H) substitution at a highly conserved residue in the S4 segment in domain IV of the channel, which contains the voltage-sensing region. The mutation in the first family (AAD-SAL-233) was found by linkage analysis combined with whole-exome sequencing and was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family and was not found in the dbSNP (build 137), Exome Variant Server, or ExAC databases. The mutations in the other 2 families (AAD-GRE-319 and AAD-SAL-454) were found by screening of a large number of probands with a similar disorder; the mutation segregated with the phenotype in both families. Haplotype analysis excluded a founder effect all 3 families. In vitro functional expression studies in HEK293T cells showed that the mutation resulted in a significant shift of the steady-state activation curve towards more positive membrane potential values, whereas the inactivation curve had a higher slope factor. These electrophysiologic studies and computer modeling simulations suggested that mutation resulted in decreased neuronal excitability.
Morino et al. (2015) identified heterozygosity for the R1715H mutation in the CACNA1G gene in affected members of 2 unrelated Japanese families with SCA42. The mutations were found by linkage analysis and exome sequencing and were confirmed by Sanger sequencing. The mutation segregated with the disorder in both families, which shared a haplotype containing the mutation. Electrophysiologic studies showed that the mutation shifted the activation to more positive (depolarized) membrane potentials. Inactivation potentials were also shifted to more positive membrane potentials, although the slope factor was not significantly different. The findings indicated that SCA42 is a channelopathy.
In 3 unrelated girls (subjects 1, 3, and 4) with early-onset severe spinocerebellar ataxia-42 with neurodevelopmental deficits (SCA42ND; 618087), Chemin et al. (2018) identified a recurrent de novo heterozygous c.2881G-A transition (c.2881G-A, NM_018896.4) in the CACNA1G gene, resulting in an ala961-to-thr (A961T) substitution at a highly conserved residue within the S6 segment that contributes to the pore lining of the channel. The mutation in the first patient was found by whole-exome sequencing and confirmed by Sanger sequencing. The other patients were identified through collaborative sharing of patients with a similar phenotype who underwent exome sequencing. The mutation was not found in the ExAC database. Electrophysiologic studies in HEK293 cells showed that the mutation had markedly slowed inactivation kinetics compared to wildtype and caused increased calcium influx, consistent with a gain of function. Computational modeling of the mutations confirmed that the mutation would promote increased firing activity in deep cerebellar neurons.
In a girl (subject 2) with early-onset severe spinocerebellar ataxia-42 with neurodevelopmental deficits (SCA42ND; 618087), Chemin et al. (2018) identified a de novo heterozygous c.4591A-G transition (c.4591A-G, NM_018896.4) in the CACNA1G gene, resulting in a met1531-to-val (M1531V) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. Electrophysiologic studies in HEK293 cells showed that the mutation had markedly slowed inactivation kinetics compared to wildtype and caused increased calcium influx, consistent with a gain of function. Computational modeling of the mutations confirmed that the mutation would promote increased firing activity in deep cerebellar neurons.
Chemin, J., Monteil, A., Perez-Reyes, E., Bourinet, E., Nargeot, J., Lory, P. Specific contribution of human T-type calcium channel isotypes (alpha-1G, alpha-1H, and alpha-1I) to neuronal excitability. J. Physiol. 540: 3-14, 2002. [PubMed: 11927664] [Full Text: https://doi.org/10.1113/jphysiol.2001.013269]
Chemin, J., Siquier-Pernet, K., Nicouleau, M., Barcia, G., Ahmad, A., Medina-Cano, D., Hanein, S., Altin, N., Hubert, L., Bole-Feysot, C., Fourage, C., Nitschke, P., and 17 others. De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene. Brain 141: 1998-2013, 2018. [PubMed: 29878067] [Full Text: https://doi.org/10.1093/brain/awy145]
Coutelier, M., Blesneac, I., Monteil, A., Monin, M.-L., Ando, K., Mundwiller, E., Brusco, A., Le Ber, I., Anheim, M., Castrioto, A., Duyckaerts, C., Brice, A., Durr, A., Lory, P., Stevanin, G. A recurrent mutation in CACNA1G alters Cav3.1 T-type calcium-channel conduction and causes autosomal-dominant cerebellar ataxia. Am. J. Hum. Genet. 97: 726-737, 2015. [PubMed: 26456284] [Full Text: https://doi.org/10.1016/j.ajhg.2015.09.007]
Jagannathan, S., Punt, E. L., Gu, Y., Arnoult, C., Sakkas, D., Barratt, C. L. R., Publicover, S. J. Identification and localization of T-type voltage-operated calcium channel subunits in human male germ cells: expression of multiple isoforms. J. Biol. Chem. 277: 8449-8456, 2002. [PubMed: 11751928] [Full Text: https://doi.org/10.1074/jbc.M105345200]
Kim, D., Park, D., Choi, S., Lee, S., Sun, M., Kim, C., Shin, H.-S. Thalamic control of visceral nociception mediated by T-type Ca(2+) channels. Science 302: 117-119, 2003. [PubMed: 14526084] [Full Text: https://doi.org/10.1126/science.1088886]
Kim, D., Song, I., Keum, S., Lee, T., Jeong, M.-J., Kim, S.-S., McEnery, M. W., Shin, H.-S. Lack of the burst firing of thalamocortical relay neurons and resistance to absence seizures in mice lacking alpha-1G T-type Ca(2+) channels. Neuron 31: 35-45, 2001. [PubMed: 11498049] [Full Text: https://doi.org/10.1016/s0896-6273(01)00343-9]
Morino, H., Matsuda, Y., Mugurama, K., Miyamoto, R., Ohsawa, R., Ohtake, T., Otobe, R., Watanabe, M., Maruyama, H., Hashimoto, K., Kawakami, H. A mutation in the low voltage-gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia. Molec. Brain 8: 89, 2015. Note: Electronic Article. [PubMed: 26715324] [Full Text: https://doi.org/10.1186/s13041-015-0180-4]
Perez-Reyes, E., Cribbs, L. L., Daud, A., Lacerda, A. E., Barclay, J., Williamson, M. P., Fox, M., Rees, M., Lee, J.-H. Molecular characterization of a neuronal low-voltage-activated T-type calcium channel. Nature 391: 896-900, 1998. [PubMed: 9495342] [Full Text: https://doi.org/10.1038/36110]