Alternative titles; symbols
HGNC Approved Gene Symbol: CHRNA4
Cytogenetic location: 20q13.33 Genomic coordinates (GRCh38): 20:63,343,223-63,361,349 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.33 | {Nicotine addiction, susceptibility to} | 188890 | 3 | |
| Epilepsy, nocturnal frontal lobe, 1 | 600513 | Autosomal dominant | 3 |
The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The nAChRs are thought to be (hetero)pentamers composed of homologous subunits. See 118508 for additional background information on nAChRs.
Monteggia et al. (1995) obtained the full-length cDNA sequence for the alpha-4 neuronal nicotinic acetylcholine receptor subunit. The predicted amino acid sequence is 89% similar to the rat sequence, with most differences in the cytoplasmic domain. Elliott et al. (1996) also cloned the alpha-4 gene.
Steinlein et al. (1996) determined that the CHRNA4 gene consists of 6 exons distributed over approximately 17 kb of genomic DNA.
By genomic Southern blot analysis of hamster/human somatic cell hybrid DNAs, Anand and Lindstrom (1992) mapped the gene encoding the alpha-4 subunit of the human neuronal nicotinic acetylcholine receptor to chromosome 20. Pilz et al. (1992) likewise mapped the gene to human chromosome 20 by Southern blot analysis of human/rodent somatic cell hybrids. The corresponding gene is located on chromosome 2 in the mouse (Bessis et al., 1990).
By fluorescent in situ hybridization, Steinlein et al. (1994) positioned CHRNA4 on a contig between D20S24 and D20S20 on chromosome 20q13.2-q13.3. The 2 markers were separated by 160 kb. Steinlein et al. (1994) suggested that the location of CHRNA4 made it a possible candidate gene for either benign neonatal familial convulsions (EBN1; 121200) or the electroencephalographic variant pattern 1 (EEGV1; 130180).
Monteggia et al. (1995) found that transfection of expression vectors for the alpha-4 and beta-2 (CHRNB2; 118507) nAChR subunits into HEK293 cells resulted in the formation of binding sites with the expected high affinity for cytosine.
Elliott et al. (1996) demonstrated that human alpha-4 encodes a functional receptor when expressed in combination with human beta-2 or beta-4 (CHRNB4; 118509) in Xenopus oocytes.
By immunoprecipitation analysis of mouse striatal extracts, Champtiaux et al. (2003) identified 3 main types of heteromeric nAChRs: alpha-4/beta-2, alpha-6 (CHRNA6; 606888)/beta-2, and alpha-4/alpha-6/beta-2. Alpha-6/beta-2 nAChRs were mainly located on dopamine (DA) nerve terminals and were the direct target of alpha-conotoxin MII inhibition. A combination of alpha-6/beta-2 and alpha-4/beta-2 nAChRs mediated endogenous cholinergic modulation of DA release induced by systemic nicotine administration at nerve terminals. Alpha-4/beta-2 nAChRs appeared to represent the majority of nAChRs on DA neuron soma and contributed to nicotine reinforcement.
Crystal Structure
Xiu et al. (2009) showed that at the brain acetylcholine receptors alpha-4 (CHRNA4)-beta-2 (CHRNB2) thought to underlie nicotine addiction, the high affinity for nicotine is the result of a strong cation-pi interaction to a specific aromatic amino acid of the receptor, TrpB. In contrast, the low affinity for nicotine at the muscle-type acetylcholine receptor is largely due to the absence of this key interaction, even though the immediate binding site residues, including the key amino acid TrpB, are identical in the brain and muscle receptors. At the same time a hydrogen bond from nicotine to the backbone carbonyl of TrpB is enhanced in the neuronal receptor relative to the muscle type. A point mutation near TrpB that differentiates alpha-4-beta-2 and muscle-type receptors seems to influence the shape of the binding site, allowing nicotine to interact more strongly with TrpB in the neuronal receptor.
Cryoelectron Microscopy
Walsh et al. (2018) used cryoelectron microscopy to obtain structures for the alpha-4-beta-2 nicotinic acetylcholine receptor in both the 2-alpha-to-3-beta and 3-alpha-to-2-beta stoichiometries from a single sample. The antibody fragments specific to beta-2 were used to break symmetry during particle alignment and to obtain high-resolution reconstructions of receptors of both stoichiometries in complex with nicotine. The results revealed principles of subunit assembly and the structural basis of the distinctive biophysical and pharmacologic properties of the 2 different stoichiometries of this receptor.
Nocturnal Frontal Lobe Epilepsy 1
Steinlein et al. (1995) demonstrated a missense mutation in the CHRNA4 gene (S252F; 118504.0002) associated with autosomal dominant nocturnal frontal lobe epilepsy (ENFL1; 600513), which had previously been mapped to 20q. The mutation was sought because CHRNA4 maps to the candidate region of 20q and the gene is expressed in all layers of the frontal cortex. Mutations in the CHRNA4 gene appear to account for only a small proportion of the cases of nocturnal frontal lobe epilepsy.
Associations with Other Disorders
Nicotine is the major addictive substance in cigarettes, and genes involved in sensing nicotine are logical candidates for vulnerability to nicotine addiction (188890). Feng et al. (2004) studied 6 single-nucleotide polymorphisms (SNPs) in the CHRNA4 gene and 4 SNPs in the CHRNB2 gene (118507) in relation to nicotine dependence in a collection of 901 subjects (815 sibs and 86 parents) from 222 nuclear families with multiple nicotine-addicted sibs. They found 2 SNPs in exon 5 of the CHRNA4 gene to be significantly associated with a protective effect against nicotine addiction. Furthermore, a common (22.5%) CHRNA4 haplotype was significantly associated with a protective effect against nicotine addiction.
Li et al. (2005) analyzed 6 SNPs within CHRNA4 for association with nicotine dependence (ND). In a sample of European American families, SNPs rs2273504 and rs1044396 (118504.0005) were significantly associated with the adjusted smoking quantity and Fagerstrom test for ND score, respectively. In the African American families, SNPs rs3787137 and rs2236196 were each significantly associated with at least 2 adjusted ND measures. Haplotype analysis of rs2273505, rs2273504, and rs2236196 showed significant association after Bonferroni correction of a C-G-G haplotype (53.4%) with 3 adjusted ND measures in samples from the African American females.
For a possible association between variation in the CHRNA4 gene and the psychologic trait of harm avoidance, see 607834.
Benign familial neonatal seizures 1 (BFNS1; 121200) was shown to be caused by mutations in the KCNQ2 gene (602235), which also maps to chromosome 20q13 (Singh et al., 1998). The finding of a presumed mutation (Beck et al., 1994) in the CHRNA4 gene, which maps to the same region, in 1 of 20 families, was presumably an error.
Marubio et al. (1999) disrupted the alpha-4 subunit of the neuronal nicotinic acetylcholine receptor by homologous recombination and studied homozygous alpha-4-null mice and mice lacking the beta-2 subunit of the nAChR. The homozygous alpha-4 -/- mice no longer expressed high-affinity nicotine binding sites throughout the brain. In addition, both types of mutant mice displayed a reduced antinociceptive effect of nicotine on the hot-plate test and diminished sensitivity to nicotine in the tail-flick test. Patch-clamp recordings revealed that raphe magnus and thalamic neurons no longer responded to nicotine. Marubio et al. (1999) stated that the alpha-4 nAChR subunit, thought to associate with the beta-2 nAChR subunit, is therefore crucial for nicotine-elicited antinociception.
The electroconvulsive threshold (ECT) test has been used extensively to determine the protection conferred by antiepileptic drug candidates against induced seizures in rodents. Yang et al. (2003) adopted the ECT test to screen the progeny of ethylnitrosourea-treated male C57BL/6J mice. In a small-scale screen, several mutant lines conferring a low threshold to ECT minimal clonic seizures were mapped to the telomeric region of mouse chromosome 2 in independent founder families. Genetic and physical mapping data indicated that several lines shared a single mutation, Szt1 (seizure threshold-1), consisting of a 300-kb deletion of genomic DNA involving 3 known genes. Two of these genes, Kcnq2 and Chrna4, are known to be mutated in human epilepsy families. Szt1 homozygotes and heterozygotes displayed similar phenotypes to those found in the respective Kcnq2 knockout mutant mice, suggesting that Kcnq2 haploinsufficiency may lie at the root of the Szt1 seizure sensitivity.
Tapper et al. (2004) generated mutant mice with alpha-4 nicotinic subunits containing a single point mutation, leu9-prime to ala, in the pore-forming M2 domain, rendering alpha-4 mutant receptors hypersensitive to nicotine. Selective activation of alpha-4 mutant nicotinic acetylcholine receptors with low doses of agonist recapitulated nicotine effects thought to be important in dependence, including reinforcement in response to acute nicotine administration, as well as tolerance and sensitization elicited by chronic nicotine administration. Tapper et al. (2004) concluded that activation of alpha-4 mutant receptors is sufficient for nicotine-induced reward, tolerance, and sensitization.
Klaassen et al. (2006) generated 2 mouse models of autosomal dominant nocturnal frontal lobe epilepsy by introducing an S252F (118504.0002) mutation or a leu264 insertion in the Chrna4 gene, respectively. Mice heterozygous for the S252F mutation or the leu264 insertion showed abnormal cortical EEGs with prominent delta and theta frequencies, frequent spontaneous seizures, and increased sensitivity to the proconvulsant action of nicotine. Voltage-clamp studies showed that a considerable fraction of mutant Chrna4-containing nAChRs were located on presynaptic terminals of cortical GABAergic interneurons and that activation of these receptors resulted in elevated presynaptic calcium levels. The results were consistent with a model of epileptogenesis in which acetylcholine significantly enhances cortical GABAergic transmission, which contributes to epileptogenesis through inhibitory resetting and synchronization of neural networks.
In affected members of a large Australian kindred with autosomal dominant nocturnal frontal lobe epilepsy (ENFL1; 600513) reported by Phillips et al. (1995), Steinlein et al. (1995) used single-strand conformation analysis to identify a C-to-T transition in exon 5 of the CHRNA4 gene, resulting in ser248-to-phe (SER248PHE) substitution in the sixth amino acid position of transmembrane domain 2 (M2) and reduced receptor function. Their numbering was based on the Torpedo californica Chrna4 sequence. Saenz et al. (1999) noted that in the human sequence codon 252 is homologous to the Torpedo codon 248, and they referred to the mutation as ser252 to phe (S252F).
Forman et al. (1996) suggested an alternative mechanism for pathogenesis of epilepsy associated with this CHRNA4 mutation. From studies of the mouse muscle alpha-1 nicotinic receptor (100690) noted in Forman et al. (1995), Forman et al. (1996) speculated that the mutation in CHRNA4 may cause receptor hyperactivity that could lead to epileptic activity.
In 11 affected members of a large Spanish family with nocturnal frontal lobe epilepsy, Saenz et al. (1999) identified the S252F mutation. Saenz et al. (1999) noted that the clinical features were similar to those reported by Steinlein et al. (1995). This same residue is affected in the S252L mutation (118504.0004)
Using PET scans, Fedi et al. (2008) observed decreased striatal D1 receptor (DRD1; 126449) binding, particularly in the right putamen, in 12 individuals with autosomal dominant nocturnal frontal lobe epilepsy and the S252L mutation compared to controls. Decreased D1 receptor binding was postulated to represent receptor downregulation from increased extracellular levels of dopamine. Increased dopamine release may result from a gain-of-function in nAChRs with the mutant CHRNA4 subunit, since nAChRs regulate dopamine release.
In a Norwegian family with autosomal dominant nocturnal frontal lobe epilepsy (ENFL1; 600513), Steinlein et al. (1997) identified a 3-bp (GCT) insertion at nucleotide position 776 into the region of the CHRNA4 gene coding for the C-terminal end of the M2 domain. Physiologic investigations of the receptor reconstituted with the mutated CHRNA4 subunit revealed that this insertion does not prevent the receptor function but increases its apparent affinity for acetylcholine. In addition, this mutant receptor showed a significantly lower calcium permeability that, at the cellular level, may correspond to a loss of function.
In a Japanese family with autosomal dominant nocturnal frontal lobe epilepsy (ENFL1; 600513), Hirose et al. (1999) identified a 755C-T transition in exon 5 of the CHRNA4 gene, causing a ser252-to-leu (S252L) substitution. The mutation was not found in 200 alleles of healthy volunteers. Based on analysis of the amino acid sequence, Hirose et al. (1999) suggested that the serine-to-leucine change undermines the channel function considerably.
In a Korean family in which 9 members in 3 generations were affected with ENFL1, Cho et al. (2003) identified the S252L mutation. Cho et al. (2003) noted that the clinical phenotype in the Korean family was similar to that reported by Hirose et al. (1999) in the Japanese family with the same mutation. Shared features included mental retardation and drug resistance.
This same residue is affected in the S252F mutation (118504.0002).
By haplotype analysis, Hwang et al. (2011) determined that the common mutation identified by Hirose et al. (1999) and Cho et al. (2003), which Hwang et al. (2011) referred to as ser284-to-leu (S284L), did not arise from a common founder, but rather occurred independently. The mutation was associated with a CpG hypermutable site.
Feng et al. (2004) found a single-nucleotide polymorphism in exon 5 of the CHRNA4 gene, rs1044396, to be significantly associated with a protective effect against nicotine addiction (188890). The C-to-T transition is synonymous (ser-ser). The variant T allele is the protective allele.
Feng et al. (2004) found a single-nucleotide polymorphism in exon 5 of the CHRNA4 gene, rs1044397, to be significantly associated with a protective effect against nicotine addiction (188890). The G-to-A transition is synonymous (ala-ala). The variant A allele is the protective allele.
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