Alternative titles; symbols
HGNC Approved Gene Symbol: CHRNE
Cytogenetic location: 17p13.2 Genomic coordinates (GRCh38): 17:4,897,771-4,908,677 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.2 | Myasthenic syndrome, congenital, 4A, slow-channel | 605809 | Autosomal dominant; Autosomal recessive | 3 |
| Myasthenic syndrome, congenital, 4B, fast-channel | 616324 | Autosomal recessive | 3 | |
| Myasthenic syndrome, congenital, 4C, associated with acetylcholine receptor deficiency | 608931 | Autosomal recessive | 3 |
Acetylcholine receptors (AChRs) at mature mammalian neuromuscular junctions (NMJs) are pentameric protein complexes composed of 4 subunits in the ratio of 2 alpha subunits (CHRNA1; 100690) to 1 beta (CHRNB1; 100710), 1 epsilon, and 1 delta subunit (CHRND; 100720). Most, if not all, embryonic AChRs contain a different subunit, gamma (CHRNG; 100730), in place of the epsilon subunit. It is likely that this change in subunit composition, which occurs during the first 2 weeks after birth, accounts for the switch in properties of ACh-activated channels from low-conductance, long open time to high-conductance, brief open time that occurs over approximately the same time course. In neonatal mouse and rat myotubes, epsilon-subunit mRNA is present at low levels, whereas gamma-subunit mRNA is present at relatively high levels. During the first 2 weeks after birth, the amount of epsilon-subunit mRNA rises 10-fold and gamma-subunit mRNA falls to undetectable levels. The increase in epsilon-subunit mRNA appears to be confined to the developing motor endplate. The switch to the epsilon subunit is mediated by ARIA (acetylcholine receptor-inducing activity; 142445).
Beeson et al. (1993) isolated cDNA sequences encompassing the full coding region of the CHRNE and CHRNG genes. The deduced amino acid sequences indicated that the mature epsilon subunit contains 473 amino acids and is preceded by a 20-amino acid signal peptide. In common with the human alpha, beta, gamma, and delta subunits, the epsilon subunit is highly conserved among mammalian species.
Witzemann et al. (1996) noted that in mammalian muscle the functional properties of endplate channels change during postnatal development. The length of channel-opening bursts decreases and, as a consequence, the duration of miniature endplate current (mEPC) decreases, whereas the conductance and the Ca(2+) permeability of endplate channels increase. The underlying molecular mechanism is a switch in the expression of acetylcholine receptor subunit genes shortly after birth. The gamma-subunit (CHRNG) is repressed while the epsilon-subunit gene is activated selectively in the myonuclei underlying the synapse. To investigate the significance of the CHRNG/CHRNE switch for motor behavior, Witzemann et al. (1996) ablated the Chrne gene in mouse embryonic stem cells by homologous recombination and injected correctly engineered cells of 2 independently isolated clones into C57BL/6 blastocysts. Chimeric male mice derived from both clones showed germline transmission of the targeted allele. Homozygous mutant animals showed that after apparently normal development in early neonatal life, neuromuscular transmission was progressively impaired. The lack of epsilon subunits caused muscle weakness, defects in motor behavior, and premature death 2 to 3 months after birth. Their results demonstrated that postnatal incorporation of epsilon subunits in acetylcholine receptors into the endplate is essential for normal development of skeletal muscle.
By recording images at liquid-helium temperatures and applying a computational method to correct for distortions, Miyazawa et al. (2003) determined 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.
Dan et al. (2002) found that the terminal exons of the MINK1 (609426) and CHRNE genes overlap in a tail-to-tail manner on opposite DNA strands in hominoid genomes, but not in the mouse. They suggested that the potentially hazardous mutations responsible for the exon overlap managed to escape evolutionary pressures by differential temporospatial expression of the 2 genes.
Lobos (1993) concluded that the CHRNE gene is located about 5 cM from the CHRNB1 gene (100710) in the vicinity of TP53 (191170) on 17p13.1. Using linkage analysis, the conclusion was confirmed by hybridization of CHRNE and CHRNB1 probes to a panel of human/hamster somatic cell hybrids. CHRNB1 was previously assigned to 17p12-p11. By PCR analysis of somatic cell hybrids, Beeson et al. (1993) demonstrated that the CHRNE gene is located on chromosome 17.
Slow-Channel Congenital Myasthenic Syndrome 4A
In a woman with slow-channel congenital myasthenic syndrome-4A (CMS4A; 605809), Ohno et al. (1995) identified a heterozygous missense mutation in the CHRNE gene (T264P; 100725.0001).
Fast-Channel Congenital Myasthenic Syndrome 4B
In 2 unrelated patients with fast-channel congenital myasthenic syndrome-4B (CMS4B; 616324), 1 of whom had been reported by Uchitel et al. (1993), Ohno et al. (1996) identified compound heterozygosity for 2 mutations in the CHRNE gene. Both patients shared a heterozygous P121L (100725.0003) mutation, which caused a marked decrease in the rate of AChR channel opening, a reduction in the frequency of the open channel state, and resistance to desensitization by ACh. Each patient carried a different pathogenic mutation in the CHRNE gene on the other allele (G-8R, 100725.0017 and S143L, 100725.0018).
In a male patient with CMS4B, Webster et al. (2014) identified compound heterozygous mutations in the CHRNE gene: a c.43T-C transition, resulting in a tyr15-to-his substitution (Y15H), and a c.113C-A transversion, resulting in a thr38-to-lys substitution (T38K).
Among 32 patients with congenital myasthenic syndrome with episodic apnea, McMacken et al. (2018) were able to confirm 14 cases genetically, including one 6-year-old boy (case 17) with CMS4B who was compound heterozygous for the same mutations in the CHRNE gene that were identified in a patient reported by Webster et al. (2014): Y15H and T38K.
Congenital Myasthenic Syndrome 4C Associated with Acetylcholine Receptor Deficiency
In a patient with congenital myasthenic syndrome-4C associated with AChR deficiency (CMS4C; 608931), Engel et al. (1996) identified compound heterozygosity for two 1-bp insertions in the CHRNE gene (100725.0013 and 100725.0014).
Ohno et al. (1997) described and functionally characterized mutations of the CHRNE gene (see, e.g., 100725.0004;100725.0005; 100725.0015; 100725.0016) in 3 patients with congenital myasthenic syndrome due to AChR deficiency.
Sieb et al. (2000) demonstrated biallelic CHRNE mutations (see, e.g., 100725.0006 and 100725.0007) in affected members of 2 previously reported families with congenital myasthenic syndrome and AChR deficiency (Sieb et al., 1998). Immunohistochemistry in these cases revealed reduced expression of utrophin (UTRN; 128240) at the endplates.
Among 5 Dutch patients with congenital myasthenic syndrome associated with AChR deficiency, Ealing et al. (2002) identified 4 mutations in the CHRNE gene. The mutations were located in the 18-amino acid epsilon subunit C terminus, which lies extracellular to the M4 transmembrane domain of the AChR. The authors transfected cells with GFP-tagged mutant or wildtype AChR epsilon subunits. AChR-containing wildtype GFP-tagged subunits were incorporated into the surface membrane, whereas the GFP-tagged AChR mutant subunits colocalized with an endoplasmic reticulum (ER) marker and were not expressed on the cell surface. In addition, mutant AChRs did not reach the cell surface, as measured by radiolabeling of intact cells and precipitation with an epsilon subunit-specific antiserum. Mutagenesis studies showed that the cysteine at codon 470, located 4 amino acids from the C terminus, is essential for alpha/epsilon assembly and surface expression of adult AChR. Change of codon 470 to serine did not restore alpha/epsilon assembly or surface expression.
Kraner et al. (2002) determined the genetic defect in 4 previously reported related Brahman calves with severe myasthenia weakness (Thompson, 1998). They demonstrated homozygosity for a 20-bp deletion in exon 5 of the CHRNE gene that caused a frameshift followed by a premature stop codon. The survival time was limited to only a few months, indicating that the effect on neuromuscular transmission was more pronounced in the calves than that observed in humans homozygous for truncating CHRNE mutations. Kraner et al. (2002) speculated that this might be due to a different capacity to express the fetal-type AChR after birth.
Cossins et al. (2004) generated transgenic mice that constitutively expressed CHRNG in a Chrne-knockout background. These mice, in which neuromuscular transmission is mediated by fetal AChR, lived well into adulthood but showed striking similarities to human AChR deficiency syndrome. They displayed fatigable muscle weakness, reduced miniature endplate potentials and endplate potentials, reduced motor endplate AChR number, and altered endplate morphology.
Groshong et al. (2007) found that mice with the L269F (100725.0002) mutation showed muscle weakness, fatigability, and impaired neuromuscular transmission, similar to the human disorder. Muscle fibers from mutant mice showed significantly increased levels of the calcium-activated cysteine protease calpain (see, e.g., CAPN3; 114240) at the neuromuscular junction. Calpain levels were dependent on synaptic activity and activation of mutant AChR, and diminished with blockade of AChR. Transgenic expression of the natural calpain inhibitor calpastatin (CAST; 114090) reduced calpain to baseline, normalized the size of the neuromuscular junction and the endplate current frequency, and improved strength and neuromuscular transmission. The protective effect of CAST appeared to be due to a strengthening of synaptic connections, rather than a protective effect on mutant AChRs. There was persistent endplate myopathy in CAST-null/L269F double-mutant mice associated with ongoing activation of caspase family proteases, such as CASP3 (600636), that are not inhibited by calpastatin.
In a 20-year-old woman with slow-channel congenital myasthenic syndrome-4A (CMS4A; 605809), Ohno et al. (1995) identified a heterozygous c.790A-C transversion at nucleotide 790 in exon 8 of the CHRNE gene, resulting in a thr264-to-pro (T264P) substitution at a highly conserved residue in the M2 transmembrane domain lining the channel pore. Genetically engineered mutant T264P AChR expressed in a human embryonic kidney fibroblast cell line showed markedly prolonged channel openings in the presence of agonist, as well as opening in the absence of agonist.
In 3 affected members of a family with slow-channel congenital myasthenic syndrome-4A (CMS4A; 605809), Gomez and Gammack (1995) identified heterozygosity for a C-to-T transition in the CHRNE gene, resulting in a leu269-to-phe (L269F) substitution within the M2 transmembrane domain of the protein.
In a 16-year-old male with CMS4A, Engel et al. (1996) identified a heterozygous c.805C-T transition in exon 8 of the CHRNE gene, resulting in the L269F substitution at a conserved residue in the M2 transmembrane domain that lines that AChR channel pore. Functional expression studies showed that the L269F mutation slowed the rate of AChR channel closure and increased the apparent affinity for ACh. The mutation also caused pathologic channel openings even in the absence of ACh, resulting in a leaky channel. Cationic overload of the postsynaptic region caused an endplate myopathy.
In 2 unrelated patients with fast-channel congenital myasthenic syndrome-4B (CMS4B; 616324), 1 of whom had been reported by Uchitel et al. (1993), Ohno et al. (1996) identified compound heterozygosity for 2 mutations in the CHRNE gene. Both patients shared a heterozygous c.362C-T transition in exon 5, resulting in a pro121-to-leu (P121L) substitution at a conserved residue in the extracellular domain of the subunit. Functional expression studies showed that the P121L mutation caused a marked decrease in the rate of AChR channel opening (nearly 500-fold slower compared to controls), a reduction in the frequency of the open channel state, and resistance to desensitization by ACh. One patient also had a heterozygous c.-24G-A transition (100725.0017), resulting in a gly(-8)-to-arg (G-8R) substitution in the signal peptide region; the other patient had a heterozygous c.428C-T transition in exon 5 of the CHRNE gene, resulting in a ser143-to-leu (S143L; 100725.0018) substitution in a conserved N-glycosylation consensus sequence of the protein. Both of these mutations were determined to be null mutations, with the clinical phenotype defined by the P121L mutation.
In a patient with congenital myasthenic syndrome-4C associated with AChR deficiency (CMS4C; 608931), Ohno et al. (1997) identified compound heterozygosity for 2 mutations in the CHRNE gene: a c.190C-T transition that converted an arginine codon to a TGA stop codon at position 64 (R64X), and a c.440G-T transversion predicted to result in an arg147-to-leu (R147L; 100725.0005) substitution. An affected brother had both mutations; the asymptomatic mother had the R64X allele and the asymptomatic father and brother had the R147L allele. The mutated arginine (R64X) is conserved across epsilon subunits of other species, but not in other subunits. R64X predicted truncation of the epsilon subunit in its extracellular domain, and expression studies in human embryonic kidney fibroblasts (HEK cells) indicated that it was a null mutation. The R147L mutation significantly reduced AChR expression.
For discussion of the arg147-to-leu (R147L) mutation in the CHRNE gene that was found in compound heterozygous state in a patient with congenital myasthenic syndrome-4C associated with acetylcholine receptor deficiency (CMS4C; 608931) by Ohno et al. (1997), see 100725.0004.
Sieb et al. (2000) found that a brother and sister with congenital myasthenic syndrome-4C associated with AChR deficiency (CMS4C; 608931) were compound heterozygotes for a 1-bp deletion (c.911delT) and a splice site mutation (IVS4+1G-A; 100725.0007) in the CHRNE gene. Both mutations resulted in truncation of the protein. The family had previously been reported by Sieb et al. (1998).
In a patient with a mild form of postsynaptic congenital myasthenic syndrome, Muller et al. (2005) identified compound heterozygosity for 2 mutations in the CHRNE gene: c.911delT and a splice site mutation (100725.0020).
For discussion of the IVS4+1G-A mutation in the CHRNE gene that was found in compound heterozygous state in a patient with congenital myasthenic syndrome-4C associated with AChR deficiency (CMS4C; 608931) by Sieb et al. (2000), see 616146.0006.
In a 30-year-old woman with congenital myasthenic syndrome-4C associated with AChR deficiency (CMS4C; 608931), Sieb et al. (2000) found compound heterozygosity for a novel c.1030delC mutation and the previously described R64X mutation (100725.0004).
In 2 unrelated families with a mild form of slow-channel congenital myasthenic syndrome-4A (CMS4A; 605809), Croxen et al. (2002) identified a heterozygous c.661C-T transition in the CHRNE gene, resulting in a leu221-to-phe (L221F) substitution located near the extracellular end of the M1 domain of the AChRE subunit. The authors hypothesized that the mutation may enhance the affinity of the AChRE subunit for ACh. The 2 pedigrees showed different inheritance patterns: in 1 family, all members with the mutation were affected, whereas in the other family, 2 members with the mutation were clinically unaffected, thus illustrating incomplete penetrance. The patients had previously been reported by Oosterhuis et al. (1987) and Chauplannaz and Bady (1994).
In 2 sibs, born of consanguineous parents, with congenital myasthenic syndrome-4C associated with AChR deficiency (CMS4C; 608931), Nichols et al. (1999) identified a homozygous c.156C-T transition in the CHRNE promoter region (termed the N-box). Both parents were heterozygous for the mutation. Intercostal muscle biopsy from 1 patient showed loss of expression of the AChR-epsilon mRNA. Nichols et al. (1999) stated that this was the first evidence in humans that an N-box mutation can lead to disruption of epsilon subunit transcription.
In 13 patients from 11 Gypsy families with congenital myasthenic syndrome-4C associated with AChR deficiency (CMS4C; 608931), Abicht et al. (1999) identified a homozygous 1-bp deletion in exon 12 of the CHRNE gene (c.1267delG). All families were of Gypsy or southeastern European origin. Genotype analysis indicated that they derived from a common ancestor.
In patients from India and Pakistan with CMS and AChR deficiency, Croxen et al. (1999) identified the 1267delG mutation in exon 12 of the CHRNE gene.
Middleton et al. (1999) identified a homozygous c.1267delG mutation in affected members of 5 families with CMS4C previously reported by Christodoulou et al. (1997). Four of the families were of Gypsy descent.
Morar et al. (2004) used the 1267delG mutation and 4 other private mutations among the Roma (Gypsies) to infer some of the missing parameters relevant to the comprehensive characterization of the population history of the Gypsies. Sharing of mutations and high carrier rates supported a strong founder effect. The identity of the congenital myasthenia 1267delG mutation in Gypsy and Indian/Pakistani chromosomes provided strong evidence for the Indian origins of the Gypsies. Hantai et al. (2004) reported a carrier rate of 3.74% for the 1267delG mutation in these ethnic groups.
In a patient with congenital myasthenic syndrome-4C associated with AChR deficiency (CMS4C; 608931), Engel et al. (1996) identified compound heterozygosity for two 1-bp insertions in the CHRNE gene: c.1101insT and c.1293insG (100725.0014). Both mutations predict premature termination of the protein between the third (M3) and fourth (M4) transmembrane domains. The patient's asymptomatic son carried the 1293insG mutation. Functional expression studies of both mutations showed a marked reduction of AChR expression. Engel et al. (1996) found that the patient expressed the fetal AChR gamma subunit (CHRNG; 100730), which likely served as a means of phenotypic rescue.
Richard et al. (2008) identified a homozygous 1-bp insertion (c.1293insG) in the CHRNE gene in 14 (60%) of 23 North African families with congenital myasthenic syndrome-4C associated with AChR deficiency (CMS4C; 608931). All 14 families were consanguineous; 9 originated from Algeria, 3 from Tunisia, and 1 each from Morocco and Libya. Haplotype analysis indicated a founder effect that occurred about 700 years ago. The phenotype was relatively homogeneous without fetal involvement and with moderate hypotonia and oculobulbar involvement, mild and stable disease course, and good response to cholinesterase inhibitors.
For discussion of the 1293insG mutation in the CHRNE gene that was found in compound heterozygous state in a patient with CMS4C by Engel et al. (1996), see 100725.0013.
In a patient with congenital myasthenic syndrome-4C associated with AChR deficiency (CMS4C; 608931), Ohno et al. (1997) identified compound heterozygosity for 2 mutations in the CHRNE gene: a 7-bp deletion (c.553del7), resulting in a truncated protein, and a c.931C-T transition in exon 9, resulting in an arg311-to-trp (R311W; 100725.0016) substitution. One of these 2 mutations was found in heterozygous state in several asymptomatic family members. Functional expression studies showed that the R311W mutation had a mild fast-channel kinetic effect on the AChR by shortening the long burst and increasing the decay of the endplate current.
For discussion of the arg311-to-trp (R311W) mutation in the CHRNE gene that was found in compound heterozygous state in a patient with congenital myasthenic syndrome-4C associated with AChR deficiency (CMS4C; 608931) by Ohno et al. (1996), see 100725.0015.
For discussion of the gly(-8)-to-arg (G-8R) mutation in the CHRNE gene that was found in compound heterozygous state in a patient with fast-channel congenital myasthenic syndrome-4B (CMS4B; 616324) by Ohno et al. (1996), see 100725.0003. Functional expression studies showed that the G-8R mutant CHRNE shows impaired association with the alpha (CHRNA1; 100690) subunit of the AChR.
For discussion of the ser143-to-leu (S143L) mutation in the CHRNE gene that was found in compound heterozygous state in a patient with fast-channel congenital myasthenic syndrome-4B (CMS4B; 616324) by Ohno et al. (1996), see 100725.0003. Functional expression studies showed that the S143L mutant CHRNE fails to assemble with the alpha (CHRNA1; 100690) subunit of the AChR.
In 4 affected patients from 3 unrelated families with fast-channel congenital myasthenic syndrome-4B (CMS4B; 616324) Wang et al. (2000) identified a c.1231G-C transversion in the CHRNE gene, resulting in an ala411-to-pro (A411P) substitution in the cytoplasmic domain known as the amphipathic helix, which spans the M3 and M4 transmembrane domains. Two patients were homozygous for the mutation, and 2 patients were compound heterozygous with another null mutation in CHRNE. Functional expression studies showed that the A411P mutation caused an increase in the distributions of rates for channel opening and closing, increasing the range of activation kinetics. Using structural modeling, Wang et al. (2000) concluded that the energy landscape of the AChR is shaped like a funnel, with corrugations running perpendicular to the long axis of the funnel.
In a patient with a mild form of congenital myasthenic syndrome-4C associated with AChR deficiency (CMS4C; 608931), Muller et al. (2005) identified compound heterozygosity for 2 mutations in the CHRNE gene: a G-to-A transition in intron 5, resulting in a premature termination codon after 19 amino acids in the extracellular part of the protein, and a 1-bp deletion (100725.0006). However, detailed RNA analysis showed that the patient had 4 CHRNE mRNA transcripts differing at the exon 5/exon 6 boundary, 2 of which were generated by use of a cryptic donor site in exon 5.
In an 8-year-old boy, born of consanguineous parents, with fast-channel congenital myasthenic syndrome-4B (CMS4B; 616324), Shen et al. (2012) identified a homozygous c.163T-C transition in the CHRNE gene, resulting in a trp55-to-arg (W55R) substitution at a highly conserved residue at the alpha/epsilon ACh-binding site interface. The patient had severe myasthenic symptoms since birth and was wheelchair-bound. Three similarly affected sibs died in infancy, and he had 1 similarly affected brother. In vitro functional expression in HEK293 cells showed that the mutant protein was expressed, but patch-clamp recordings indicated 30-fold reduced ACh affinity and 75-fold reduced apparent gating efficiency. The mutation hindered isomerization of the receptor from the closed to the open state, slowed the apparent opening rate, accelerated the apparent closing rate, and reduced open channel probability. These altered channel kinetics predicted a short duration and low amplitude of the endplate potential with an inability to activate postsynaptic sodium channels. There was also a low opening probability of the mutant receptor over a range of ACh concentrations, which explained the limited clinical response to pyridostigmine that was observed in this patient.
Croxen et al. (2002) reported a rare example of a patient with recessively inherited slow-channel congenital myasthenic syndrome-4A (CMS4A; 605809), born of consanguineous Bangladeshi parents, who presented with failure to breathe after administration of an anesthetic. She had bilateral ptosis and weakness of facial, neck, shoulder, hip, and small muscles of the hand. Molecular analysis revealed compound heterozygosity for 2 mutations in the CHRNE gene: ser278del on 1 allele and an arg217-to-leu substitution (R217L; 100725.0023) on the other. (In the original publication, Croxen et al. (2002) erroneously stated that this patient had a homozygous c.233T-C transition in the CHRNE gene, resulting in a leu78-to-pro (L78P) substitution in an extracellular region of the AChRE subunit.)
For discussion of the arg217-to-leu (R217L) mutation in the CHRNE gene that was found in compound heterozygous state in a patient with autosomal recessive slow-channel congenital myasthenic syndrome-4A (CMS4A; 605809) by Croxen et al. (2002), see 100725.0022.
Abicht, A., Stucka, R., Karcagi, V., Herczegfalvi, A., Horvath, R., Mortier, W., Schara, U., Ramaekers, V., Jost, W., Brunner, J., Janssen, G., Seidel, U., Schlotter, B., Muller-Felber, W., Pongratz, D., Rudel, R., Lochmuller, H. A common mutation (epsilon1267delG) in congenital myasthenic patients of Gypsy ethnic origin. Neurology 53: 1564-1569, 1999. [PubMed: 10534268] [Full Text: https://doi.org/10.1212/wnl.53.7.1564]
Beeson, D., Brydson, M., Betty, M., Jeremiah, S., Povey, S., Vincent, A., Newsom-Davis, J. Primary structure of the human muscle acetylcholine receptor cDNA cloning of the gamma and epsilon subunits. Europ. J. Biochem. 215: 229-238, 1993. [PubMed: 7688301] [Full Text: https://doi.org/10.1111/j.1432-1033.1993.tb18027.x]
Chauplannaz, G., Bady, B. Hereditary myasthenic syndromes with late onset: value of electrophysiological tests. Rev. Neurol. 150: 142-148, 1994. [PubMed: 7863154]
Christodoulou, K., Tsingis, M., Deymeer, F., Serdaroglu, P., Ozdemir, C., Al-Shehab, A., Bairactaris, C., Mavromatis, I., Mylonas, I., Evoli, A., Kyriallis, K., Middleton, L. T. Mapping of the familial infantile myasthenia (congenital myasthenic syndrome type Ia) gene to chromosome 17p with evidence of genetic homogeneity. Hum. Molec. Genet. 6: 635-640, 1997. [PubMed: 9097970] [Full Text: https://doi.org/10.1093/hmg/6.4.635]
Cossins, J., Webster, R., Maxwell, S., Burke, G., Vincent, A., Beeson, D. A mouse model of AChR deficiency syndrome with a phenotype reflecting the human condition. Hum. Molec. Genet. 13: 2947-2957, 2004. [PubMed: 15471888] [Full Text: https://doi.org/10.1093/hmg/ddh320]
Croxen, R., Hatton, C., Shelley, C., Brydson, M., Chauplannaz, G., Oosterhuis, H., Vincent, A., Newsom-Davis, J., Colquhoun, D., Beeson, D. Recessive inheritance and variable penetrance of slow-channel congenital myasthenic syndromes. Neurology 59: 162-168, 2002. Note: Partial Retraction: Neurology 72: 294 only, 2009. [PubMed: 12141316] [Full Text: https://doi.org/10.1212/wnl.59.2.162]
Croxen, R., Newland, C., Betty, M., Vincent, A., Newsom-Davis, J., Beeson, D. Novel functional epsilon-subunit polypeptide generated by a single nucleotide deletion in acetylcholine receptor deficiency congenital myasthenic syndrome. Ann. Neurol. 46: 639-647, 1999. [PubMed: 10514102] [Full Text: https://doi.org/10.1002/1531-8249(199910)46:4<639::aid-ana13>3.0.co;2-1]
Dan, I., Watanabe, N. M., Kajikawa, E., Ishida, T., Pandey, A., Kusumi, A. Overlapping of MINK and CHRNE gene loci in the course of mammalian evolution. Nucleic Acids Res. 30: 2906-2910, 2002. [PubMed: 12087176] [Full Text: https://doi.org/10.1093/nar/gkf407]
Ealing, J., Webster, R., Brownlow, S., Abdelgany, A., Oosterhuis, H., Muntoni, F., Vaux, D. J., Vincent, A., Beeson, D. Mutations in congenital myasthenic syndromes reveal an epsilon subunit C-terminal cysteine, C470, crucial for maturation and surface expression of adult AChR. Hum. Molec. Genet. 11: 3087-3096, 2002. [PubMed: 12417530] [Full Text: https://doi.org/10.1093/hmg/11.24.3087]
Engel, A. G., Ohno, K., Bouzat, C., Sine, S. M., Griggs, R. C. End-plate acetylcholine receptor deficiency due to nonsense mutations in the epsilon subunit. Ann. Neurol. 40: 810-817, 1996. [PubMed: 8957026] [Full Text: https://doi.org/10.1002/ana.410400521]
Engel, A. G., Ohno, K., Milone, M., Wang, H.-L., Nakano, S., Bouzat, C., Pruitt, J. N., II, Hutchinson, D. O., Brengman, J. M., Bren, N., Sieb, J. P., Sine, S. M. New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome. Hum. Molec. Genet. 5: 1217-1227, 1996. [PubMed: 8872460] [Full Text: https://doi.org/10.1093/hmg/5.9.1217]
Gomez, C. M., Gammack, J. T. A leucine-to-phenylalanine substitution in the acetylcholine receptor ion channel in a family with the slow-channel syndrome. Neurology 45: 982-985, 1995. [PubMed: 7538206] [Full Text: https://doi.org/10.1212/wnl.45.5.982]
Groshong, J. S., Spencer, M. J., Bhattacharyya, B. J., Kudryashova, E., Vohra, B. P. S., Zayas, R., Wollmann, R. L., Miller, R. J., Gomez, C. M. Calpain activation impairs neuromuscular transmission in a mouse model of the slow-channel myasthenic syndrome. J. Clin. Invest. 117: 2903-2912, 2007. [PubMed: 17853947] [Full Text: https://doi.org/10.1172/JCI30383]
Hantai, D., Richard, P., Koenig, J., Eymard, B. Congenital myasthenic syndromes. Curr. Opin. Neurol. 17: 539-551, 2004. [PubMed: 15367858] [Full Text: https://doi.org/10.1097/00019052-200410000-00004]
Kraner, S., Sieb, J. P., Thompson, P. N., Steinlein, O. K. Congenital myasthenia in Brahman calves caused by homozygosity for a CHRNE truncating mutation. Neurogenetics 4: 87-91, 2002. [PubMed: 12481987] [Full Text: https://doi.org/10.1007/s10048-002-0134-8]
Lobos, E. A. Five subunit genes of the human muscle nicotinic acetylcholine receptor are mapped to two linkage groups on chromosomes 2 and 17. Genomics 17: 642-650, 1993. [PubMed: 7902325] [Full Text: https://doi.org/10.1006/geno.1993.1384]
Martinou, J.-C., Falls, D. L., Fischbach, G. D., Merlie, J. P. Acetylcholine receptor-inducing activity stimulates expression of the epsilon-subunit gene of the muscle acetylcholine receptor. Proc. Nat. Acad. Sci. 88: 7669-7673, 1991. [PubMed: 1881908] [Full Text: https://doi.org/10.1073/pnas.88.17.7669]
McMacken, G., Whittaker, R. G., Evangelista, T., Abicht, A., Dusl, M., Lochmuller, H. Congenital myasthenic syndrome with episodic apnoea: clinical, neurophysiological and genetic features in the long-term follow-up of 19 patients. J. Neurol. 265: 194-203, 2018. [PubMed: 29189923] [Full Text: https://doi.org/10.1007/s00415-017-8689-3]
Middleton, L., Ohno, K., Christodoulou, K., Brengman, J., Milone, M., Neocleous, V., Serdaroglu, P., Deymeer, F., Ozdemir, C., Mubaidin, A., Horany, K., Al-Shehab, A., Mavromatis, I., Mylonas, I., Tsingis, M., Zamba, E., Pantzaris, M., Kyriallis, K., Engel, A. G. Chromosome 17p-linked myasthenias stem from defects in the acetylcholine receptor epsilon-subunit gene. Neurology 53: 1076-1082, 1999. [PubMed: 10496269] [Full Text: https://doi.org/10.1212/wnl.53.5.1076]
Miyazawa, A., Fujiyoshi, Y., Unwin, N. Structure and gating mechanism of the acetylcholine receptor pore. Nature 423: 949-955, 2003. [PubMed: 12827192] [Full Text: https://doi.org/10.1038/nature01748]
Morar, B., Gresham, D., Angelicheva, D., Tournev, I., Gooding, R., Guergueltcheva, V., Schmidt, C., Abicht, A., Lochmuller, H., Tordai, A., Kalmar, L., Nagy, M., and 10 others. Mutation history of the Roma/Gypsies. Am. J. Hum. Genet. 75: 596-609, 2004. [PubMed: 15322984] [Full Text: https://doi.org/10.1086/424759]
Muller, J. S., Stucka, R., Neudecker, S., Zierz, S., Schmidt, C., Huebner, A., Lochmuller, H., Abicht, A. An intronic base alteration of the CHRNE gene leading to a congenital myasthenic syndrome. Neurology 65: 463-465, 2005. [PubMed: 16087917] [Full Text: https://doi.org/10.1212/01.wnl.0000172346.26219.fd]
Nichols, P., Croxen, R., Vincent, A., Rutter, R., Hutchinson, M., Newsom-Davis, J., Beeson, D. Mutation of the acetylcholine receptor epsilon-subunit promoter in congenital myasthenic syndrome. Ann. Neurol. 45: 439-443, 1999. [PubMed: 10211467]
Ohno, K., Hutchinson, D. O., Milone, M., Brengman, J. M., Bouzat, C., Sine, S. M., Engel, A. G. Congenital myasthenic syndrome caused by prolonged acetylcholine receptor channel openings due to a mutation in the M2 domain of the epsilon subunit. Proc. Nat. Acad. Sci. 92: 758-762, 1995. [PubMed: 7531341] [Full Text: https://doi.org/10.1073/pnas.92.3.758]
Ohno, K., Quiram, P. A., Milone, M., Wang, H.-L., Harper, M. C., Pruitt, J. N., II, Brengman, J. M., Pao, L., Fischbeck, K. H., Crawford, T. O., Sine, S. M., Engel, A. G. Congenital myasthenic syndromes due to heteroallelic nonsense/missense mutations in the acetylcholine receptor epsilon subunit gene: identification and functional characterization of six new mutations. Hum. Molec. Genet. 6: 753-766, 1997. [PubMed: 9158150] [Full Text: https://doi.org/10.1093/hmg/6.5.753]
Ohno, K., Wang, H.-L., Milone, M., Bren, N., Brengman, J. M., Nakano, S., Quiram, P., Pruitt, J. N., Sine, S. M., Engel, A. G. Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor epsilon subunit. Neuron 17: 157-170, 1996. [PubMed: 8755487] [Full Text: https://doi.org/10.1016/s0896-6273(00)80289-5]
Oosterhuis, H. J. G. H., Newsom-Davis, J., Wokke, J. H. J., Molenaar, P. C., Weerden, T. V., Oen, B. S., Jennekens, F. G. I., Veldman, H., Vincent, A., Wray, D. W., Prior, C., Murray, N. M. F. The slow channel syndrome: two new cases. Brain 110: 1061-1079, 1987. [PubMed: 3651795] [Full Text: https://doi.org/10.1093/brain/110.4.1061]
Richard, P., Gaudon, K., Haddad, H., Ben Ammar, A., Genin, E., Bauche, S., Paturneau-Jouas, M., Muller, J. S., Lochmuller, H., Grid, D., Hamri, A., Nouioua, S., and 11 others. The CHRNE 1293insG founder mutation is a frequent cause of congenital myasthenia in North Africa. Neurology 71: 1967-1972, 2008. [PubMed: 19064877] [Full Text: https://doi.org/10.1212/01.wnl.0000336921.51639.0b]
Shen, X.-M., Brengman, J. M., Edvardson, S., Sine, S. M., Engel, A. G. Highly fatal fast-channel syndrome caused by AChR-epsilon subunit mutation at the agonist binding site. Neurology 79: 449-454, 2012. [PubMed: 22592360] [Full Text: https://doi.org/10.1212/WNL.0b013e31825b5bda]
Sieb, J. P., Dorfler, P., Tzartos, S., Wewer, U. M., Ruegg, M. A., Meyer, D., Baumann, I., Lindemuth, R., Jakschik, J., Ries, F. Congenital myasthenic syndromes in two kinships with end-plate acetylcholine receptor and utrophin deficiency. Neurology 50: 54-61, 1998. Note: Erratum: Neurology 50: 838 only, 1998. [PubMed: 9443457] [Full Text: https://doi.org/10.1212/wnl.50.1.54]
Sieb, J. P., Kraner, S., Rauch, M., Steinlein, O. K. Immature end-plates and utrophin deficiency in congenital myasthenic syndrome caused by epsilon-AChR subunit truncating mutations. Hum. Genet. 107: 160-164, 2000. [PubMed: 11030414] [Full Text: https://doi.org/10.1007/s004390000359]
Thompson, P. N. Suspected congenital myasthenia gravis in Brahman calves. Vet. Rec. 143: 526-529, 1998. [PubMed: 9839364] [Full Text: https://doi.org/10.1136/vr.143.19.526]
Uchitel, O., Engel, A. G., Walls, T. J., Nagel, A., Atassi, M. Z., Bril, V. Congenital myasthenic syndromes: II: syndrome attributed to abnormal interaction of acetylcholine with its receptor. Muscle Nerve 16: 1293-1301, 1993. [PubMed: 8232384] [Full Text: https://doi.org/10.1002/mus.880161205]
Wang, H.-L., Ohno, K., Milone, M., Brengman, J. M., Evoli, A., Batocchi, A.-P., Middleton, L. T., Christodoulou, K., Engel, A. G., Sine, S. M. Fundamental gating mechanism of nicotinic receptor channel revealed by mutation causing a congenital myasthenic syndrome. J. Gen. Physiol. 116: 449-460, 2000. [PubMed: 10962020] [Full Text: https://doi.org/10.1085/jgp.116.3.449]
Webster, R., Liu, W. W., Chaouch, A., Lochmuller, H., Beeson, D. Fast-channel congenital myasthenic syndrome with a novel acetylcholine receptor mutation at the alpha-epsilon subunit interface. Neuromusc. Disord. 24: 143-147, 2014. [PubMed: 24295813] [Full Text: https://doi.org/10.1016/j.nmd.2013.10.009]
Witzemann, V., Schwarz, H., Koenen, M., Berberich, C., Villarroel, A., Wernig, A., Brenner, H. R., Sakmann, B. Acetylcholine receptor epsilon-subunit deletion causes muscle weakness and atrophy in juvenile and adult mice. Proc. Nat. Acad. Sci. 93: 13286-13291, 1996. [PubMed: 8917583] [Full Text: https://doi.org/10.1073/pnas.93.23.13286]