[en] OBJECTIVE: Mutation analysis of the acetylcholine receptor (AChR) epsilon subunit gene in patients with sporadic or autosomal recessive congenital myasthenic syndromes (CMS). BACKGROUND: The nicotinic AChR of skeletal muscle is a neurotransmitter-gated ion channel that mediates synaptic transmission at the vertebrate neuromuscular junction. Mutations in its gene may cause congenital myasthenic syndromes. A recently described mutation in exon 12 of the AChR epsilon subunit (epsilon1267delG) disrupts the cytoplasmic loop and the fourth transmembrane region (M4) of the AChR epsilon subunit. METHODS: Forty-three CMS patients from 35 nonrelated families were clinically classified as sporadic cases of CMS (group III according to European Neuromuscular Centre consensus) and were analyzed for epsilon1267delG by PCR amplification and sequence analysis. RESULTS: The authors report the complete genomic sequence and organization of the gene coding for the epsilon subunit of the human AChR (accession number AF105999). Homozygous epsilon1267delG was identified in 13 CMS patients from 11 independent families. All epsilon1267delG families were of Gypsy or southeastern European origin. Genotype analysis indicated that they derive from a common ancestor (founder) causing CMS in the southeastern European Gypsy population. Phenotype analysis revealed a uniform pattern of clinical features including bilateral ptosis and mild to moderate fatigable weakness of ocular, facial, bulbar, and limb muscles. CONCLUSIONS: The mutation epsilon1267delG might be frequent in European congenital myasthenic syndrome patients of Gypsy ethnic origin. In general, patients (epsilon1267delG) were characterized by the onset of symptoms in early infancy, the presence of ophthalmoparesis, positive response to anticholinesterase treatment, and the benign natural course of the disease.
Disciplines :
Pediatrics Neurology
Author, co-author :
Abicht, A.; Genzentrum und Friedrich-Baur-Institut, LMU München, Germany
Stucka, R.; Genzentrum und Friedrich-Baur-Institut, LMU München, Germany
Karcagi, V.; the Department of Biochemistry, National Institute of Environmental Health, Budapest
Herczegfalvi, A.; Heim Pal Pediatric Hospital, Budapest, Hungary
Horvath, R.; Genzentrum und Friedrich-Baur-Institut, LMU München, Germany
Mortier, W.; Universitätskinderklinik und Neuromuskuläres Labor, Ruhr-Universität Bochum, Germany
Schara, U.; Universitätskinderklinik und Neuromuskuläres Labor, Ruhr-Universität Bochum, Germany
RAMAEKERS, Vincent ; he Neuropädiatrie (Dr. Ramaekers), Rheinisch-Westfälische Technische Hochschule Aachen, Germany
Jost, W.; the Universitätsklinik für Kinder und Jugendmedizin, Homburg/Saar, Germany
Brunner, J.; the Universitätsklinik für Kinder und Jugendmedizin, Homburg/Saar, Germany
Janssen, G.; the Neuropädiatrie, Universitätskinderklinik, Heinrich-Heine Universität, Düsseldorf, Germany
Seidel, U.; the Klinik für Pädiatrie mit Schwerpunkt Neurologie, Universitätsklinikum Charité, Berlin, Germany
Schlotter, B.; Genzentrum und Friedrich-Baur-Institut, LMU München, Germany
Muller-Felber, W.; Genzentrum und Friedrich-Baur-Institut, LMU München, Germany
Pongratz, D.; Genzentrum und Friedrich-Baur-Institut, LMU München, Germany
Rudel, R.; the Abt. für Allgemeine Physiologie, Universität Ulm, Germany
Lochmuller, H.; Genzentrum und Friedrich-Baur-Institut, LMU München, Germany
Karlin A, Akabas MH. Toward a structural basis for the function of nicotinic acetylcholine receptors and their cousins. Neuron 1995;15:1231-1244.
Hall ZW, Sanes JR. Synaptic structure and development: the neuromuscular junction. Cell 1993;72:99-121.
Duclert A, Changeux JP. Acetylcholine receptor gene expression at the developing neuromuscular junction. Physiol Rev 1995;75:339-368.
Noda M, Furutani Y, Takahashi H, et al. Cloning and sequence analysis of calf cDNA and human genomic DNA encoding alpha-subunit precursor of muscle acetylcholine receptor. Nature 1983;305:818-823.
Beeson D, Brydson M, Betty M, et al. Primary structure of the human muscle acetylcholine receptor: cDNA cloning of the gamma and epsilon subunits. Eur J Biochem 1993;215:229-238.
Beeson D, Brydson M, Newsom Davis J. Nucleotide sequence of human muscle acetylcholine receptor beta-subunit. Nucleic Acids Res 1989;17:4391.
Schoepfer R, Luther M, Lindstrom J. The human medulloblastoma cell line TE671 expresses a muscle-like acetylcholine receptor: cloning of the alpha-subunit cDNA. FEBS Lett 1988; 226:235-240.
Luther MA, Schoepfer R, Whiting P, et al. A muscle acetylcholine receptor is expressed in the human cerebellar medulloblastoma cell line TE671. J Neurosci 1989;9:1082-1096.
Engel AG. Myasthenic syndromes. New York: McGraw-Hill, 1994.
Walls TJ, Engel AG, Nagel AS, Harper CM, Trastek VF. Congenital myasthenic syndrome associated with paucity of synaptic vesicles and reduced quantal release. Ann NY Acad Sci 1993;681:461-468.
Mora M, Lambert EH, Engel AG. Synaptic vesicle abnormality in familial infantile myasthenia. Neurology 1987;37:206-214.
Engel AG, Lambert EH, Gomez MR. A new myasthenic syndrome with end-plate acetylcholinesterase deficiency, small nerve terminals, and reduced acetylcholine release. Ann Neurol 1977;1:315-330.
Engel AG, Lambert EH, Mulder DM, et al. A newly recognized congenital myasthenic syndrome attributed to a prolonged open time of the acetylcholine-induced ion channel. Ann Neurol 1982;11:553-569.
Uchitel O, Engel AG, Walls TJ, Nagel A, Bril V, Trastek VF. Congenital myasthenic syndrome attributed to an abnormal interaction of acetylcholine with its receptor. Ann NY Acad Sci 1993;681:487-495.
Engel AG, Hutchinson DO, Nakano S, et al. Myasthenic syndromes attributed to mutations affecting the epsilon subunit of the acetylcholine receptor. Ann NY Acad Sci 1993;681:496-508.
Engel AG, Ohno K, Sine S. Congenital myasthenic syndromes. Arch Neurol 1999;56:163-167.
Vincent A, Newland C, Croxen R, Beeson D. Genes at the junction: candidates for congenital myasthenic syndromes. Trends Neurosci 1997;20:15-22.
Beeson D, Palace J, Vincent A. Congenital myasthenic syndromes. Curr Opin Neurol 1997;10:402-407.
Ohno K, Hutchinson DO, Milone M, et al. Congenital myasthenic syndrome caused by prolonged acetylcholine receptor channel openings due to a mutation in the M2 domain of the epsilon subunit. Proc Natl Acad Sci USA 1995;92:758-762.
Sine SM, Ohno K, Bouzat C, et al. Mutation of the acetylcholine receptor alpha subunit causes a slow-channel myasthenic syndrome by enhancing agonist binding affinity. Neuron 1995; 15:229-239.
Engel AG, Ohno K, Milone M, et al. New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome. Hum Mol Genet 1996;5:1217-1227.
Gomez CM, Maselli R, Gammack J, et al. A beta-subunit mutation in the acetylcholine receptor channel gate causes severe slow-channel syndrome. Ann Neurol 1996;39:712-723.
Milone M, Wang HL, Ohno K, et al. Slow-channel myasthenic syndrome caused by enhanced activation, desensitization, and agonist binding affinity attributable to mutation in the M2 domain of the acetyleholine receptor alpha subunit. J Neurosci 1997;17:5651-5665.
Croxen R, Newland C, Beeson D, et al. Mutations in different functional domains of the human muscle acetylcholine receptor alpha subunit in patients with the slow-channel congenital myasthenic syndrome. Hum Mol Genet 1997;6:767-774.
Engel AG, Ohno K, Bouzat C, Sine SM, Griggs RC. End-plate acetylcholine receptor deficiency due to nonsense mutations in the epsilon subunit. Ann Neurol 1996;40:810-817.
Ohno K, Quiram PA, Milone M, et al. 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 Mol Genet 1997;6:753-766.
Ohno K, Anlar B, Ozdirim E, Brengman JM, DeBleecker JL, Engel AG. Myasthenic syndromes in Turkish kinships due to mutations in the acetylcholine receptor. Ann Neurol 1998;44: 234-241.
Middleton L, Christodoulou K, Brengman J, et al. Congenital myasthenic syndromes (CMS) linked to chromosome 17p are caused by defects in acetylcholine receptor (AChR) epsilon subunit gene. Neurology 1998;50:A432.
Milone M, Ohno K, Fukudome T, et al. Congenital myasthenic syndrome caused by novel loss-of-function mutations in the human AChR epsilon subunit gene. Ann NY Acad Sci 1998; 841:184-188.
Milone M, Wang HL, Ohno K, et al. Mode switching kinetics produced by a naturally occurring mutation in the cytoplasmic loop of the human acetylcholine receptor epsilon subunit. Neuron Mar 1998;20:575-588.
Middleton LT. Congenital myasthenic syndromes: 34th ENMC International Workshop, June 10-11, 1995. Neuromuscul Disord 1996;6:133-136.
Buonanno A, Mudd J, Merlie JP. Isolation and characterization of the beta and epsilon subunit genes of mouse muscle acetylcholine receptor. J Biol Chem 1989;264:7611-7616.
Quandt K, Frech K, Karas H, Wingender E, Werner T. MatInd and MatInspector: new fast and versatile tools for detection of consensus matches in nucleotide sequence data. Nucleic Acids Res 1995;23:4878-4884.
Herlitze S, Villarroel A, Witzemann V, Koenen M, Sakmann B. Structural determinants of channel conductance in fetal and adult rat muscle acetylcholine receptors. J Physiol Lond 1996;492:775-787.
Shibahara S, Kubo T, Perski HJ, Takahashi H, Noda M, Numa S. Cloning and sequence analysis of human genomic DNA encoding gamma subunit precursor of muscle acetylcholine receptor. Eur J Biochem 1985;146:15-22.
Croxen R, Beeson D, Newland C, Betty M, Vincent A, Newsom Davis J. A single nucleotide deletion in the epsilon subunit of the acetylcholine receptor (AChR) in five congenital myasthenic syndrome patients with AChR deficiency. Ann NY Acad Sci 1998;841:195-198.
Abicht A, Müller-Felber W, Fischer P, et al. Congenital myasthenic syndromes: clinical and genetic analysis of 18 patients. Eur J Med Res 1997;2:515-522.
Goldhammer Y, Blatt I, Sadeh M, Goodman RM. Congenital myasthenia associated with facial malformations in Iraqi and Iranian Jews: A new genetic syndrome. Brain 1990;113:1291-1306.
Piccolo F, Jeanpierre M, Leturcq F, et al. A founder mutation in the gamma-sarcoglycan gene of Gypsies possibly predating their migration out of India. Hum Mol Genet 1996;5:2019-2022.
