caa a22 4500 397574592 CHVBK 20180308164851.0 cr unu---uuuuu 161202e199609 xx s 000 0 eng 10.1093/hmg/5.9.1217 doi (NATIONALLICENCE)oxford-10.1093/hmg/5.9.1217 New Mutations in Acetylcholine Receptor Subunit Genes Reveal Heterogeneity in the Slow-Channel Congenital Myasthenic Syndrome [Elektronische Daten] [Andrew G. Engel, Kinji Ohno, Margherita Milone, Hai-Long Wang, Satoshi Nakano, Cecilia Bouzat, J. Ned Pruitt, David O. Hutchinson, Joan M. Brengman, Nina Bren, Joern P. Sieb, Steven M. Sine] Mutations in genes encoding the ε, δ, β and α subunits of the end plate acetylcholine (ACh) receptor (AChR) are described and functionally characterized in three slow-channel congenital myasthenic syndrome patients. All three had prolonged end plate currents and AChR channel opening episodes and an end plate myopathy with loss of AChR from degenerating junctional folds. Genetic analysis revealed heterozygous mutations: εL269F and δQ267E in Patient 1, βV266M in Patient 2, and αN217K in Patient 3 that were not detected in 100 normal controls. Patients 1 and 2 have no similarly affected relatives; in Patient 3, the mutation cosegregates with the disease in three generations. εL269F, δQ267E and βV266M occur in the second and αN217K in the first transmembrane domain of AChR subunits; all have been postulated to contribute to the lining of the upper half of the channel lumen and all but δQ267E are positioned toward the channel lumen, and introduce an enlarged side chain. Expression studies in HEK cells indicate that all of the mutations express normal amounts of AChR. εL269F, βV266M, and αN217K slow the rate of channel closure in the presence of ACh and increase apparent affinity for ACh; εL269F and αN217K enhance desensitization, and εL269F and βV266M cause pathologic channel openings in the absence of ACh, rendering the channel leaky. δQ267E has none of these effects and is therefore a rare polymorphism or a benign mutation. The end plate myopathy stems from cationic overloading of the postsynaptic region. The safety margin of neuromuscular transmission is compromised by AChR loss from the junctional folds and by a depolarization block owing to temporal summation of prolonged end plate potentials at physiologic rates of stimulation. © 1996 Oxford University Press Engel Andrew G. Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut Ohno Kinji Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut Milone Margherita Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut Wang Hai-Long Department of Physiology and Biophysics and Receptor Biology Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut Nakano Satoshi Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut Bouzat Cecilia Department of Physiology and Biophysics and Receptor Biology Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut Pruitt J. Ned Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut Hutchinson David O. Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut Brengman Joan M. Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut Bren Nina Department of Physiology and Biophysics and Receptor Biology Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut Sieb Joern P. Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut Sine Steven M. Department of Physiology and Biophysics and Receptor Biology Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut Human Molecular Genetics Oxford University Press 5/9(1996-09), 1217-1227 0964-6906 5:9<1217 1996 5 hmg https://doi.org/10.1093/hmg/5.9.1217 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1093/hmg/5.9.1217 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Engel Andrew G. Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut NATIONALLICENCE 700 1- Ohno Kinji Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut NATIONALLICENCE 700 1- Milone Margherita Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut NATIONALLICENCE 700 1- Wang Hai-Long Department of Physiology and Biophysics and Receptor Biology Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut NATIONALLICENCE 700 1- Nakano Satoshi Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut NATIONALLICENCE 700 1- Bouzat Cecilia Department of Physiology and Biophysics and Receptor Biology Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut NATIONALLICENCE 700 1- Pruitt J. Ned Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut NATIONALLICENCE 700 1- Hutchinson David O. Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut NATIONALLICENCE 700 1- Brengman Joan M. Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut NATIONALLICENCE 700 1- Bren Nina Department of Physiology and Biophysics and Receptor Biology Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut NATIONALLICENCE 700 1- Sieb Joern P. Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut NATIONALLICENCE 700 1- Sine Steven M. Department of Physiology and Biophysics and Receptor Biology Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA aut NATIONALLICENCE 773 0- Human Molecular Genetics Oxford University Press 5/9(1996-09), 1217-1227 0964-6906 5:9<1217 1996 5 hmg Metadata rights reserved CC BY-NC-4.0 http://creativecommons.org/licenses/by-nc/4.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-oxford