Alternative titles; symbols
HGNC Approved Gene Symbol: CHRNA2
Cytogenetic location: 8p21.2 Genomic coordinates (GRCh38) : 8:27,459,756-27,479,261 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p21.2 | Epilepsy, nocturnal frontal lobe, type 4 | 610353 | Autosomal dominant | 3 |
The CHRNA2 gene encodes an alpha subunit of the neuronal nicotinic cholinergic receptor (nAChR) (summary by Conti et al., 2015).
Elliott et al. (1996) cloned CHRNA2 from a thalamus cDNA library following low-stringency screening with the rat alpha-4-1 probe. The deduced 503-amino acid protein has a calculated molecular mass of 56.9 kD and contains a signal peptide, 3 N-glycosylation sites, and 4 transmembrane regions. The human and rat proteins share 84% sequence identity.
Aridon et al. (2006) found high expression of CHRNA2 mRNA in human thalamus, with lower levels of expression throughout other regions of the brain.
By genomic Southern analysis of hamster/human somatic cell hybrid DNAs, Anand and Lindstrom (1992) mapped the gene encoding the alpha-2 subunit of the human neuronal nicotinic acetylcholine receptor to chromosome 8. The corresponding gene is located on chromosome 14 in the mouse (Bessis et al., 1990).
Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, Dorus et al. (2004) examined the evolution of genes involved in diverse aspects of nervous system biology. These genes, including CHRNA2, displayed significantly higher rates of protein evolution in primates than in rodents. This trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. Dorus et al. (2004) concluded that the phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development.
In all 10 affected members of a Sardinian family with autosomal dominant nocturnal frontal lobe epilepsy-4 (ENFL4; 610353), Aridon et al. (2006) identified a heterozygous missense mutation in the CHRNA2 gene (I279N; 118502.0001). One unaffected family member carried the mutation, indicating incomplete penetrance.
In 7 affected members of a large family with ENFL4, Conti et al. (2015) identified a heterozygous missense mutation in the CHRNA2 gene (I297F; 118502.0002). The mutation, which was found by targeted sequencing of 150 probands with a similar disorder, segregated with the disorder in the family. In vitro functional expression studies in HEK293 cells showed that the heterozygous mutation resulted in a reduction in current density to about 40% of wildtype values. Homozygosity for the mutation resulted in no measurable currents. These findings were consistent with a loss of receptor function.
In affected members of a family with familial infantile seizures-6 (BFIS6; see 610353), Trivisano et al. (2015) identified a heterozygous missense mutation in the CHRNA2 gene (R376W; 118502.0003). The mutation, which was found by targeted sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
Lotfipour et al. (2017) found that mice transfected with a mutant Chrna2 gene (L9'S) that created a hypersensitive nAChR showed impaired learning and memory in a dorsal hippocampal-dependent task of contextual fear conditioning. The learning deficits could be rescued with nicotine. Electrophysiologic studies showed that the hypersensitive AChR with mutant Chrna2 potentiated ACh-induced ion channel flux as well as increased acute nicotine-induced facilitation of long-term potentiation. In contrast, Chrna2-null mice showed a baseline deficit in learning that was not reversed by nicotine. The findings indicated that nACh receptors containing Chrna2 can influence hippocampal-dependent learning and memory, and that nicotine may play a role in synaptic plasticity.
In all 10 affected members of a Sardinian family with autosomal dominant nocturnal frontal lobe epilepsy-4 (ENFL4; 610353), Aridon et al. (2006) identified a heterozygous 836T-A transversion in exon 6 of the CHRNA2 gene, resulting in an ile279-to-asn (I279N) substitution in a conserved residue in the first transmembrane domain (M1) of the protein. The mutation was not identified in 340 control chromosomes. In vitro functional expression studies showed that the I279N mutation markedly increased receptor sensitivity to acetylcholine. Aridon et al. (2006) emphasized that ictal fear sensations in this family suggested frontolimbic involvement.
In 7 affected members of a large family with autosomal dominant nocturnal frontal lobe epilepsy-4 (ENFL4; 610353), Conti et al. (2015) identified a heterozygous c.889A-T transversion (c.889A-T, NM_000742.3) in the CHRNA2 gene, resulting in an ile297-to-phe (I297F) substitution at a conserved residue in the second transmembrane domain. The mutation, which was found by targeted sequencing of 150 probands with a similar disorder, segregated with the disorder in the family. It was not found in the Exome Variant Server or ExAC databases. In vitro functional expression studies in HEK293 cells showed that the heterozygous mutation resulted in a reduction in current density to about 40% of wildtype values. Homozygosity for the mutation resulted in no measurable currents. These findings were consistent with a loss of receptor function.
In a father and his 2 daughters with benign familial infantile seizures-6 (BFIS6; see 610353), Trivisano et al. (2015) identified a heterozygous c.1126C-T transition in the CHRNA2 gene, resulting in an arg376-to-trp (R376W) substitution in the cytoplasmic domain. The mutation, which was found by targeted sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP or Exome Variant Server databases, or in 188 matched controls. Functional studies of the variant and studies of patient cells were not performed.
Anand, R., Lindstrom, J. Chromosomal localization of seven neuronal nicotinic acetylcholine receptor subunit genes in humans. Genomics 13: 962-967, 1992. [PubMed: 1505988] [Full Text: https://doi.org/10.1016/0888-7543(92)90008-g]
Aridon, P., Marini, C., Di Resta, C., Brilli, E., De Fusco, M., Politi, F., Parrini, E., Manfredi, I., Pisano, T., Pruna, D., Curia, G., Cianchetti, C., Pasqualetti, M., Becchetti, A., Guerrini, R., Casari, G. Increased sensitivity of the neuronal nicotinic receptor alpha-2 subunit causes familial epilepsy with nocturnal wandering and ictal fear. Am. J. Hum. Genet. 79: 342-350, 2006. [PubMed: 16826524] [Full Text: https://doi.org/10.1086/506459]
Bessis, A., Simon-Chazottes, D., Devillers-Thiery, A., Guenet, J.-L., Changeux, J.-P. Chromosomal localization of the mouse genes coding for alpha-2, alpha-3, alpha-4 and beta-2 subunits of neuronal nicotinic acetylcholine receptor. FEBS Lett. 264: 48-52, 1990. [PubMed: 2338144] [Full Text: https://doi.org/10.1016/0014-5793(90)80761-7]
Conti, V., Aracri, P., Chiti, L., Brusco, S., Mari, F., Marini, C., Albanese, M., Marchi, A., Liguori, C., Placidi, F., Romigi, A., Becchetti, A., Guerrini, R. Nocturnal frontal lobe epilepsy with paroxysmal arousals due to CHRNA2 loss of function. Neurology 84: 1520-1528, 2015. [PubMed: 25770198] [Full Text: https://doi.org/10.1212/WNL.0000000000001471]
Dorus, S., Vallender, E. J., Evans, P. D., Anderson, J. R., Gilbert, S. L., Mahowald, M., Wyckoff, G. J., Malcom, C. M., Lahn, B. T. Accelerated evolution of nervous system genes in the origin of Homo sapiens. Cell 119: 1027-1040, 2004. [PubMed: 15620360] [Full Text: https://doi.org/10.1016/j.cell.2004.11.040]
Elliott, K. J., Ellis, S. B., Berckhan, K. J., Urrutia, A., Chavez-Noriega, L. E., Johnson, E. C., Velicelebi, G., Harpold, M. M. Comparative structure of human neuronal alpha-2-alpha-7 and beta-2-beta-4 nicotinic acetylcholine receptor subunits and functional expression of the alpha-2, alpha-3, alpha-4, alpha-7, beta-2, and beta-4 subunits. J. Molec. Neurosci. 7: 217-228, 1996. [PubMed: 8906617] [Full Text: https://doi.org/10.1007/BF02736842]
Lotfipour, S., Mojica, C., Nakauchi, S., Lipovsek, M., Silverstein, S., Cushman, J., Tirtorahardjo, J., Poulos, A., Elgoyhen, A. B., Sumikawa, K., Fanselow, M. S., Boulter, J. Alpha-2* nicotinic acetylcholine receptors influence hippocampus-dependent learning and memory in adolescent mice. Learn. Mem. 24: 231-244, 2017. [PubMed: 28507032] [Full Text: https://doi.org/10.1101/lm.045369.117]
Trivisano, M., Terracciano, A., Milano, T., Cappelletti, S., Pietrafusa, N., Bertini, E. S., Vigevano, F., Specchio, N. Mutation of CHRNA2 in a family with benign familial infantile seizures: potential role of nicotinic acetylcholine receptor in various phenotypes of epilepsy. Epilepsia 56: e53-e57, 2015. [PubMed: 25847220] [Full Text: https://doi.org/10.1111/epi.12967]