Alternative titles; symbols
HGNC Approved Gene Symbol: CHRNA1
SNOMEDCT: 60192008;
Cytogenetic location: 2q31.1 Genomic coordinates (GRCh38): 2:174,747,592-174,764,472 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q31.1 | Multiple pterygium syndrome, lethal type | 253290 | Autosomal recessive | 3 |
| Myasthenic syndrome, congenital, 1A, slow-channel | 601462 | Autosomal dominant | 3 | |
| Myasthenic syndrome, congenital, 1B, fast-channel | 608930 | Autosomal dominant; Autosomal recessive | 3 |
The nicotinic acetylcholine receptor (AChR) controls electrical signaling between nerve and muscle cells by opening and closing a gate, membrane-spanning pore. It has 5 subunits of 4 different types: 2 alpha and 1 each of beta, gamma (or epsilon), and delta subunits (summary by Miyazawa et al., 2003).
Noda et al. (1983) cloned cDNA for the alpha subunit precursor of the calf skeletal muscle AChR and a human genomic DNA segment containing the CHRNA1 gene. Nucleotide sequences showed marked homology with the counterpart of Torpedo sp. (electric ray).
Analyzing acetylcholine receptor clones isolated from a human leg muscle cDNA library, Beeson et al. (1990) found that the alpha subunit exists in 2 isoforms. A novel 75-nucleotide exon P3A, between exons 3 and 4, results in the insertion of 25 amino acids into the alpha subunit, giving the new isoform 462 amino acids. The transcript lacking P3A (P3A-) encodes a functional subunit, whereas the transcript containing P3A (P3A+) encodes a nonfunctional subunit. The P3A- and P3A+ transcripts are generated in a 1:1 ratio in human muscle (Masuda et al., 2008).
Schoepfer et al. (1988) showed that a human medulloblastoma cell line expressed a muscle type rather than a neuronal type of acetylcholine receptor. They succeeded in isolating cDNA clones for the alpha subunit and suggested that these should be useful in obtaining large amounts of human muscle-type acetylcholine receptor alpha-subunit protein for studies of the autoimmune response in myasthenia gravis (see 601462).
Keiger et al. (2003) surveyed the developmental expression of nicotinic receptors, including CHRNA1, in chick and human spinal cord.
Michalk et al. (2008) analyzed the expression of AChR subunits Chrna1, Chrnb1 (100710), Chrnd (100720), Chrng (100730), and the receptor-associated protein Rapsn (601592) in mouse embryos before (E10.5, E11.5) and during (E12.5, E14.5) muscle development as well as in limb sections with advanced muscle development (E15.5). All studied AChR subunits and Rapsn are expressed in somites as early as E10.5. At E11.5, expression of Chrna1, Chrnb1, Chrnd, Chrng, and Rapsn begins in the developing upper limb and proceeds proximal further into the developing muscle bulks at E12.5. At E14.5, expression corresponds to the muscle anlagen in the trunk, neck, limbs, and diaphragm. Strong expression was also detected in the nuchal musculature, including near the jugular lymphatic sac as well as in the subcutaneous muscle layers.
The protein-coding sequence of the human ACHRA gene is divided into 9 exons that correspond to different structural and functional domains of the precursor molecule (Noda et al., 1983).
Beeson et al. (1990) identified the exon P3A and found that CHNRA1 gene is alternatively spliced. Masuda et al. (2008) found that a -8G nucleotide in intron 3 is an essential nucleotide of an intronic splicing silencer (ISS) that markedly decreases recognition of exon P3A by heterogeneous nuclear ribonucleoprotein (hnRNP) H (HNRPH1; 601035). They showed that hnRNP H is the transfactor that normally binds to this ISS and suppresses expression of P3A.
By means of somatic cell hybridization, Beeson et al. (1989, 1990) assigned the CHRNA gene to chromosome 2; by in situ hybridization, they regionalized the gene to 2q24-q32, with the major peak of grains being at 2q32. By linkage analysis, Lobos (1993) placed the CHRNA gene about 27 cM proximal to the crystallin G pseudogene marker, CRYGP1, located at 2q33-q35; the CHRND (100720) and CHRNG (100730) loci were placed about 31 cM distal to CRYGP1.
Heidmann et al. (1986) mapped the mouse alpha subunit gene to chromosome 17, but Taylor and Rowe (1989) determined that the mouse Chrna1 gene is in fact located on chromosome 2.
Giraud et al. (2007) described a mechanism controlling thymic transcription of a prototypic tissue-restricted human autoantigen gene, CHRNA1. This gene encodes the alpha subunit of the muscle acetylcholine receptor, which is the main target of pathogenic autoantibodies in autoimmune myasthenia gravis (254200). On resequencing the CHRNA1 gene, Giraud et al. (2007) identified a functional biallelic variant in the promoter that was associated with early onset of disease in 2 independent human populations (France and U.K.). The authors showed that this variant prevented binding of interferon regulatory factor-8 (IRF8; 601565) and abrogated CHRNA1 promoter activity in thymic epithelial cells in vitro. Notably, both the CHRNA1 promoter variant and AIRE (607358) modulated CHRNA1 mRNA levels in human medullary thymic epithelial cells ex vivo and also in a transactivation assay. Giraud et al. (2007) concluded that their findings revealed a critical function of AIRE and the interferon signaling pathway in regulating quantitative expression of this autoantigen in the thymus, suggesting that together they set the threshold for self-tolerance versus autoimmunity.
By recording images at liquid-helium temperatures and applying a computational method to correct for distortions, Miyazawa et al. (2003) reported the crystal structure of the acetylcholine receptor of the Torpedo electric ray at a resolution of 4 angstroms. The pore is shaped by an inner ring of 5 alpha helices, which curve radially to create a tapering path for the ions, and an outer ring of 15 alpha helices, which coil around each other and shield the inner ring from the lipids. The gate is a constricting hydrophobic girdle at the middle of a lipid bilayer, formed by weak interactions between neighboring inner helices. When acetylcholine enters the ligand-binding domain, it triggers rotations of the protein chains on opposite sides of the entrance to the pore. These rotations are communicated through the inner helices and open the pore by breaking the girdle apart.
Lape et al. (2008) investigated partial agonists for 2 members of the nicotinic superfamily, the muscle nicotinic acetylcholine receptor and the glycine receptor (138491), and found that the open-shut reaction is similar for both full and partial agonists, but the response to partial agonists is limited by an earlier conformation change (flipping) that takes place when the channel is still shut. Lape et al. (2008) suggested that their observations have implications for the interpretation of structural studies and for the design of partial agonists for therapeutic use.
Myasthenia Gravis
Garchon et al. (1994) identified 2 stable polymorphic dinucleotide repeats within the first intron of the CHRNA gene, designated HB and BB. They found that the HB*14 allele conferred a relative risk for myasthenia gravis (254200) of 2.5 in 81 unrelated patients compared with 100 control subjects. Very significantly, family analysis based on haplotype segregation data indicated that parental haplotypes associated with HB*14 always segregated to the child with myasthenia gravis, whereas their transmission to unaffected sibs was as expected ('was equilibrated,' in the words of the authors). Myasthenia gravis patients always showed a high frequency of microsatellite variants not seen in controls.
Giraud et al. (2007) found that the minor allele G of rs16862847 was associated with early onset of disease in French and U.K. myasthenia gravis patients in a combined sample of 96 patients in the lower quartile of the age distribution versus 234 patients in the upper 3 quartiles of the age distribution and 260 controls (odds ratio = 2.19, 95% confidence interval 1.41 to 3.39, p = 0.00048). For heterozygotes plus homozygotes for the G allele versus homozygotes for the A allele, the odds ratio for early onset of myasthenia gravis was 2.66 (95% confidence interval 1.6 to 4.41, P = 0.00015).
Slow-Channel Congenital Myasthenic Syndrome 1A
In a patient with slow-channel congenital myasthenic syndrome-1A (CMS1A; 601462), Engel et al. (1996) identified a heterozygous missense mutation in the CHRNA1 gene (N217K; 100690.0001).
Fast-Channel Congenital Myasthenic Syndrome 1B
In 2 sibs with fast-channel congenital myasthenic syndrome-1B (CMS1B; 608930), Wang et al. (1999) identified compound heterozygosity for 2 mutations in the CHRNA gene (V285I, 100690.0007 and F233V, 100690.0008).
Lethal Multiple Pterygium Syndrome
In affected members of 2 families with lethal multiple pterygium syndrome (253290), Michalk et al. (2008) identified homozygous mutations in the CHRNA1 gene (see, e.g., 100690.0013).
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human CHRNA1 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In a 30-year-old woman with slow-channel congenital myasthenic syndrome-1A (CMS1A; 601462), Engel et al. (1996) identified a heterozygous 651C-G transversion in exon 6 of the CHRNA1 gene, resulting in an asn217-to-lys (N217K) substitution at a conserved residue in the M1 transmembrane domain. The mutation cosegregated with the disease through 3 generations. Functional expression studies showed that the N217K mutation slowed the rate of AChR channel closure, increased the apparent affinity for ACh, and enhanced desensitization. Cationic overload of the postsynaptic region caused an endplate myopathy.
In a 34-year-old man (patient 1) with slow-channel congenital myasthenic syndrome-1A (CMS1A; 601462), Croxen et al. (1997) identified a heterozygous 466G-A transition in the CHRNA1 gene, resulting in a val156-to-met (V156M) substitution in a putative ACh-binding region of the protein. Functional studies suggested that the V156M mutation stabilizes the open state of the AChR channel.
In a 60-year-old woman (patient 2) with slow-channel congenital myasthenic syndrome-1A (CMS1A; 601462), Croxen et al. (1997) identified a heterozygous 761C-T transition in the CHRNA1 gene, resulting in a thr254-to-ile (T254I) substitution in the M2 transmembrane domain, which lines the AChR channel pore. The patient, who first developed symptoms at age 16 years, was previously reported by Chauplannaz and Bady (1994). Functional expression studies suggested that the T254I mutation stabilized the open state of the AChR channel.
In 5 members of a family and another unrelated person with slow-channel congenital myasthenic syndrome-1A (CMS1A; 601462), Sine et al. (1995) identified a heterozygous 457G-A transition in the CHRNA1 gene, resulting in a gly153-to-ser (G153S) substitution in the extracellular domain of the subunit. Electrophysiologic analysis of endplates revealed prolonged decay of miniature endplate currents (MEPCs) and prolonged activation episodes of single AChR channels. Single-channel kinetic analysis of engineered alpha-G153S AChR showed a markedly decreased rate of acetylcholine dissociation, indicating an increased affinity for ACh, causing the mutant AChR to open repeatedly during ACh occupancy. In addition, ACh-binding measurements combined with the kinetic analysis indicated increased desensitization of the mutant AChR. Sine et al. (1995) concluded that ACh-binding affinity can dictate the time course of the synaptic response. The patients had previously been reported by Engel et al. (1982).
Croxen et al. (1997) identified the G153S mutation in a 41-year-old woman (patient 3) with CMS1 and her affected mother. The proband had previously been reported by Chauplannaz and Bady (1994). The G153S substitution resides in the putative ACh-binding domain of the protein, and functional expression studies suggested that the G153S mutation impedes dissociation of ACh from the AChR.
In a 28-year-old woman (patient 4) with slow-channel congenital myasthenic syndrome-1A (CMS1A; 601462) with onset in the eighth month of her first pregnancy (Oosterhuis et al., 1987), Croxen et al. (1997) identified an 806G-T transversion in the CHRNA1 gene, resulting in a ser269-to-ile (S269I) substitution. The mutation lies within the short extracellular sequence between the M2 and M3 transmembrane domains of the protein.
In a patient with a severe form of slow-channel congenital myasthenic syndrome-1A (CMS1A; 601462), Milone et al. (1997) identified a heterozygous 745G-T transversion in exon 7 of the CHRNA1 gene, resulting in a val249-to-phe (V249F) substitution in the M2 transmembrane domain of the protein that does not face the channel lumen. The patient's unaffected father was a mosaic for the mutation. Functional expression studies showed that the V249F mutation causes increased channel opening in the absence of ACh, prolonged opening in the presence of ACh, increased affinity for ACh, and enhanced desensitization. The findings indicated that the structure of the M2 domain is essential for correct stabilization of functional channel states and that mutation in this region results in multiple functional defects.
In 2 sibs with fast-channel congenital myasthenic syndrome-1B (CMS1B; 608930), Wang et al. (1999) identified compound heterozygosity for 2 mutations in the CHRNA1 gene. The functional mutation was an 853G-A transition in exon 7, resulting in a val285-to-ile (V285I) substitution in the upper third of the M3 transmembrane domain. The other mutation was a c.697T-G transversion in exon 6, resulting in a phe233-to-val substitution (F233V; 100690.0008) in the M1 transmembrane domain, causing markedly reduced protein expression; this was essentially a null mutation. Functional expression studies showed that the V285I mutation reduced the amplitude of the miniature endplate current (MEPC), accelerated the decay of the MEPC, and reduced total current flow through the AChR channel. Kinetic analysis showed abnormally slow channel opening and rapid closing, resulting in an abnormally brief current.
For discussion of the phe233-to-val (F233V) mutation in the CHRNA1 gene that was found in compound heterozygous state in a patient with fast-channel congenital myasthenic syndrome-1B (CMS1B; 608930) by Wang et al. (1999), see 100690.0007.
In a patient with fast-channel congenital myasthenic syndrome-1B (CMS1B; 608930), originally reported by Vincent et al. (1981), Webster et al. (2004) identified a heterozygous 766T-C transition in exon 7 of the CHRNA1 gene, resulting in a phe256-to-leu (F256L) substitution in the M2 transmembrane domain of the protein. Functional expression studies showed that the F256L mutation results in fewer and shorter ion channel activations, with a decreased channel- opening rate and an increased channel-closing rate. The patient's mildly affected father also had the F256L mutation. Webster et al. (2004) noted that autosomal dominant inheritance of fast-channel CMS is rare.
In a girl with severe fast-channel congenital myasthenic syndrome-1B (CMS1B; 608930), Shen et al. (2003) identified compound heterozygosity for 2 mutations in the CHRNA1 gene: a frameshifting null mutation (381delC; 100690.0011), and a 394G-C transversion, resulting in a val132-to-leu (V132L) substitution, in a highly conserved cys-loop at the junction between the extracellular ligand-binding and transmembrane domains of the protein. Functional kinetic expression studies showed that channels with the V132L mutation had an increased dissociation constant for ACh, shorter burst duration, and resistance to desensitization, culminating in a reduced probability of channel opening over a range of ACh concentrations. The mutant channel showed an approximately 30-fold decrease of ACh-binding affinity for the second of 2 closed-state binding sites, but only a 2-fold decrease in gating efficiency. Mutations corresponding to the val132 residue in other AChR subunits showed different effects, indicating functional asymmetry between cys-loops of the different subunits.
For discussion of the 381delC mutation in the CHRNA1 gene that was found in compound heterozygous state in a patient with fast-channel congenital myasthenic syndrome-1B (CMS1B; 608930) by Shen et al. (2003), see 100690.0010.
In a 24-year-old man with congenital slow-channel congenital myasthenic syndrome-1A (CMS1A; 601462) and mild symptoms since birth, Shen et al. (2006) identified a de novo heterozygous 1362C-G transversion in the CHRNA1 gene, resulting in a cys418-to-trp (C418W) substitution in the M4 domain of the protein. This residue is highly conserved across AChR-alpha subunits of different species but not across individual subunits. Functional kinetic expression studies in HEK cells showed that the AChR with the mutant alpha subunit increased the channel-opening equilibrium as well as the mean duration of open durations and bursts characteristic of a slow-channel mutation. The C418W mutant subunit increased the rate of channel opening and slowed the rate of channel closing, but had no effect on agonist binding. Shen et al. (2006) used a check plasmid as a screening tool to identify a specific siRNA that suppressed the mutant, but not the wildtype allele, at the mRNA, protein, and functional levels in vitro.
In a consanguineous Pakistani family, Michalk et al. (2008) demonstrated that multiple pterygium syndrome (253290) was caused by homozygosity for a G-to-T transversion at nucleotide 761 in exon 6 of the CHRNA1 gene that resulted in an arg234-to-leu (R234L) substitution in the mature protein (R254L in the precursor).
In a nonconsanguineous African family, Michalk et al. (2008) found that multiple pterygium syndrome (253290) was caused by homozygous duplication of 17 basepairs in exon 2 of the CHRNA1 gene, 117_133dup17, that resulted in frameshift and subsequent premature protein termination (H24RfsX19; H45RfsX19 in the precursor).
In a woman with autosomal recessive inheritance of fast-channel congenital myasthenic syndrome-1B (CMS1B; 608930), Masuda et al. (2008) identified compound heterozygosity for 2 mutations in the CHRNA1 gene: a G-to-A transition in intron 3 (IVS3-8G-A) and a 937C-T transition in exon 7, resulting in an arg313-to-trp (R313W; 100690.0016) substitution in a highly conserved residue. Neither mutation was found in 200 control alleles. Functional expression studies in HEK cells showed decreased expression of the R313W mutant, which showed mild fast-channel properties. The -8G-A transition occurred just before exon P3A, and disrupted an intronic splicing silencer (ISS) sequence, resulting in the inclusion of exon P3A and yielding a nonfunctional protein.
For discussion of the arg313-to-trp (R313W) mutation in the CHRNA1 gene that was found in compound heterozygous state in a patient with fast-channel congenital myasthenic syndrome-1B (CMS1B; 608930) by Masuda et al. (2008), see 100690.0015.
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