OMIM Browser
Detalied information of OMIM terms
OMIM No
100725
TI
*100725 CHOLINERGIC RECEPTOR, NICOTINIC, EPSILON POLYPEPTIDE; CHRNE;;ACETYLCHOLINE RECEPTOR, MUSCLE, EPSILON SUBUNIT; ACHRE
OMIM Class
Muscular
TX
DESCRIPTION Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of 4 subunits in the ratio of 2 alpha subunits (100690) to 1 beta (100710), 1 epsilon, and 1 delta subunit (100720). Most, if not all, embryonic acetylcholine receptors 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 acetylcholine-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).
CLONING
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.
GENE FUNCTION
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.
BIOCHEMICAL FEATURES
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.
GENE STRUCTURE
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.
MAPPING
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.
MOLECULAR GENETICS
In a woman with slow-channel congenital myasthenic syndrome (SCCMS; 601462), Ohno et al. (1995) identified a heterozygous mutation in the CHRNE gene (100725.0001).
In a patient with CMS associated with AChR deficiency (608931), Engel et al. (1996) identified compound heterozygosity for 2 1-bp insertions in the CHRNE gene (100725.0013; 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 CHRNE mutations 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 (128240) at the endplates.
Croxen et al. (2002) reported 2 sisters diagnosed in childhood with congenital myasthenic syndrome, each of whom was found to carry 2 mutations in the AChR epsilon-subunit gene near the N terminus. Serum anti-AChR antibody levels were negative in both patients. At the age of 34 years, the younger sister's condition deteriorated, with respiratory failure necessitating tracheostomy and assisted ventilation. Serum anti-AChR titers were elevated, indicating autoimmune myasthenia gravis (254200) and the patient was successfully treated with plasmapheresis, immunosuppression, and thymectomy. Croxen et al. (2002) suggested that the epsilon-AChR gene mutations may predispose to later development of anti-AChR antibodies. The authors also noted that the younger sister had recently had 3 children and, unlike her sister, was homozygous for the HLA-DR3-B8-A1 phenotype, which is known to associate with autoimmune myasthenia gravis.
Among 5 Dutch patients with congenital myasthenic syndrome, 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.
ANIMAL MODEL
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.
SA
Martinou et al. (1991)
RF
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. Croxen, R.; Vincent, A.; Newsom-Davis, J.; Beeson, D.: Myasthenia gravis in a woman with congenital AChR deficiency due to epsilon-subunit mutations. Neurology 58: 1563-1565, 2002.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. Hantai, D.; Richard, P.; Koenig, J.; Eymard, B.: Congenital myasthenic syndromes. Curr. Opin. Neurol. 17: 539-551, 2004.
14. 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.
15. 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.
16. 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.
17. Miyazawa, A.; Fujiyoshi, Y.; Unwin, N.: Structure and gating mechanism of the acetylcholine receptor pore. Nature 423: 949-955, 2003.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. Thompson, P. N.: Suspected congenital myasthenia gravis in Brahman calves. Vet. Rec. 143: 526-529, 1998.
28. 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.
29. 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.
30. 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.
CS
AV
| No |
Name |
Disease |
Gene |
Mutation |
| References |
Normal & Mutated sequences |
| 100725.0001 |
MYASTHENIC SYNDROME, SLOW-CHANNEL CONGENITAL |
|
CHRNE |
THR264PRO |
1. Ohno, K. et al.
|
|
|
In a 20-year-old woman with slow-channel congenital myasthenic syndrome (601462), Ohno et al. (1995) identified a heterozygous 790A-C transversion at nucleotide 790 in exon 8 of the CHRNE gene, resulting in a thr264-to-pro (T264P) substitution. The substitution is located in 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.
|
| 100725.0002 |
MYASTHENIC SYNDROME, SLOW-CHANNEL CONGENITAL |
|
CHRNE |
LEU269PHE |
1. Engel, A. G. et al.
2. Gomez, C. M. et al.
|
|
|
In 3 affected members of a family with slow-channel congenital myasthenic syndrome (601462), 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 slow-channel congenital myasthenic syndrome, Engel et al. (1996) identified a heterozygous 805C-T transition in exon 8 of the CHRNE gene, resulting in the L269F substitution in the epsilon AChR channel subunit. The substitution lies within 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.
|
| 100725.0003 |
MYASTHENIC SYNDROME, FAST-CHANNEL CONGENITAL |
|
CHRNE |
PRO121LEU |
1. Ohno, K. et al.
2. Uchitel, O. et al.
|
|
|
In 2 unrelated patients with fast-channel congenital myasthenic syndrome (608930), 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 362C-T transition in exon 5, resulting in a pro121-to-leu (P121L) substitution in 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 -24G-A transition (100725.0017), resulting in a -8gly-to-arg substitution in the signal peptide region; the other patient had a heterozygous 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.
|
| 100725.0004 |
MYASTHENIC SYNDROME, CONGENITAL, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY |
|
CHRNE |
ARG64TER |
1. Ohno, K. et al.
|
|
|
In a patient with congenital myasthenic syndrome associated with AChR deficiency (608931), Ohno et al. (1997) identified compound heterozygosity for 2 mutations in the CHRNE gene: a 190C-T transition that converted an arginine codon to a TGA stop codon at position 64 (R64X), and a 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 acetylcholine receptor expression.
|
| 100725.0005 |
MYASTHENIC SYNDROME, CONGENITAL, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY |
|
CHRNE |
ARG147LEU |
1. Ohno, K. et al.
|
|
|
See 100725.0004 and Ohno et al. (1997).
|
| 100725.0006 |
MYASTHENIC SYNDROME, CONGENITAL, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY |
|
CHRNE |
1-BP DEL, 911T |
1. Muller, J. S. et al.
2. Sieb, J. P. et al.
3. Sieb, J. P. et al.
|
|
|
Sieb et al. (2000) found that a brother and sister with congenital myasthenic syndrome and AChR deficiency (608931) were compound heterozygotes for a deletion of 911T and a splicing mutation (IVS4+1G-A; 100725.0007) in the CHRNE gene. The 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: 911delT and a splice site mutation (100725.0020).
|
| 100725.0007 |
MYASTHENIC SYNDROME, CONGENITAL, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY |
|
CHRNE |
IVS4DS, G-A, +1 |
1. Sieb, J. P. et al.
|
|
|
See 100725.0006 and Sieb et al. (2000).
|
| 100725.0008 |
MYASTHENIC SYNDROME, CONGENITAL, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY |
|
CHRNE |
1-BP DEL, 1030C |
1. Sieb, J. P. et al.
|
|
|
In a 30-year-old woman with CMS and AChR deficiency (608931), Sieb et al. (2000) found compound heterozygosity for a novel 1030delC mutation and the previously described R64X mutation (100725.0004).
|
| 100725.0009 |
MYASTHENIC SYNDROME, SLOW-CHANNEL CONGENITAL, AUTOSOMAL RECESSIVE |
|
CHRNE |
LEU78PRO |
1. Croxen, R. et al.
|
|
|
Croxen et al. (2002) reported a rare example of a patient with recessively inherited congenital myasthenic syndrome (601462), born of consanguineous 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 a homozygous 233T-C transition in the CHRNE gene, resulting in a leu78-to-pro (L78P) substitution in an extracellular region of the AChRE subunit.
|
| 100725.0010 |
MYASTHENIC SYNDROME, SLOW-CHANNEL CONGENITAL |
|
CHRNE |
LEU221PHE |
1. Croxen, R. et al.
|
|
|
In 2 unrelated families with a mild form of congenital myasthenic syndrome (601462), Croxen et al. (2002) identified a heterozygous 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 variable penetrance.
|
| 100725.0011 |
MYASTHENIC SYNDROME, CONGENITAL, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY |
|
CHRNE |
156C-T |
1. Nichols, P. et al.
|
|
|
In 2 sibs with CMS and AChR deficiency (608931), the offspring of consanguineous parents, Nichols et al. (1999) identified a homozygous 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.
|
| 100725.0012 |
MYASTHENIC SYNDROME, CONGENITAL, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY |
|
CHRNE |
1-BP DEL, 1267G |
1. Abicht, A. et al.
2. Croxen, R. et al.
3. Hantai, D. et al.
4. Morar, B. et al.
|
|
|
In 13 patients from 11 Gypsy families with CMS and AChE deficiency (608931), Abicht et al. (1999) identified a homozygous 1-bp deletion in the CHRNE gene (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. 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 of 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.
|
| 100725.0013 |
MYASTHENIC SYNDROME, CONGENITAL, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY |
|
CHRNE |
1-BP INS, 1101T |
1. Engel, A. G. et al.
|
|
|
In a patient with CMS associated with AChR deficiency (608931), Engel et al. (1996) identified compound heterozygosity for two 1-bp insertions in the CHRNE gene: 1101insT and 1293insG (100725.0014). Both mutations predict premature truncation 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.
|
| 100725.0014 |
MYASTHENIC SYNDROME, CONGENITAL, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY |
|
CHRNE |
1-BP INS, 1293G |
1. Engel, A. G. et al.
|
|
|
See 100725.0013 and Engel et al. (1996). Richard et al. (2008) identified homozygosity for the 1293insG mutation in 14 (60%) of 23 North African families with AChR deficiency (608931). All families were consanguineous, and 9 families 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.
|
| 100725.0015 |
MYASTHENIC SYNDROME, CONGENITAL, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY |
|
CHRNE |
7-BP DEL, 553 |
1. Ohno, K. et al.
|
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In a patient with CMS associated with AChR deficiency (608931), Ohno et al. (1997) identified compound heterozygosity for 2 mutations in the CHRNE gene: a 7-bp deletion (553del7), resulting in a truncated protein, and a 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 form in several asymptomatic family members. Functional expression studies showed that the R311W had a mild fast-channel kinetic effect on the AChR by shortening the long burst and increasing the decay of the endplate current.
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| 100725.0016 |
MYASTHENIC SYNDROME, CONGENITAL, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY |
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CHRNE |
ARG311TRP |
1. Ohno, K. et al.
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See 100725.0015 and Ohno et al. (1997).
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| 100725.0017 |
MYASTHENIC SYNDROME, CONGENITAL, FAST-CHANNEL |
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CHRNE |
GLY-8ARG |
1. Ohno, K. et al.
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See 100725.0003 and Ohno et al. (1996). Functional expression studies showed that the G-8R mutant CHRNE shows impaired association with the alpha (CHRNA1; 100690) subunit of the AChR.
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| 100725.0018 |
MYASTHENIC SYNDROME, CONGENITAL, FAST-CHANNEL |
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CHRNE |
SER143LEU |
1. Ohno, K. et al.
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See 100725.0003 and Ohno et al. (1996). Functional expression studies showed that the S143L mutant CHRNE fails to assemble with the alpha (CHRNA1; 100690) subunit of the AChR.
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| 100725.0019 |
MYASTHENIC SYNDROME, CONGENITAL, FAST-CHANNEL |
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CHRNE |
ALA411PRO |
1. Wang, H.-L. et al.
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In 4 affected patients from 3 unrelated families with fast-channel CMS (608930), Wang et al. (2000) identified a 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 heterozygotes 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.
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| 100725.0020 |
MYASTHENIC SYNDROME, CONGENITAL, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY |
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CHRNE |
IVS5AS, G-A, -16 |
1. Muller, J. S. et al.
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In a patient with a mild form of postsynaptic congenital myasthenic syndrome (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.
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IMS (Integrated Mutated Sequence)
Create date
2007-10-07 21:22:29
