title: Mutations Causing Slow-Channel Myasthenia Reveal That a Valine Ring in the Channel Pore of Muscle AChR is Optimized for Stabilizing Channel Gating.
abstract: We identify two novel mutations in acetylcholine receptor (AChR) causing a slow-channel congenital myasthenia syndrome (CMS) in three unrelated patients (Pts). Pt 1 harbors a heterozygous βV266A mutation (p.Val289Ala) in the second transmembrane domain (M2) of the AChR β subunit (CHRNB1). Pts 2 and 3 carry the same mutation at an equivalent site in the ε subunit (CHRNE), εV265A (p.Val285Ala). The mutant residues are conserved across all AChR subunits of all species and are components of a valine ring in the channel pore, which is positioned four residues above the leucine ring. Both βV266A and εV265A reduce the amino acid size and lengthen the channel opening bursts by fourfold by enhancing gating efficiency by approximately 30-fold. Substitution of alanine for valine at the corresponding position in the δ and α subunit prolongs the burst duration four- and eightfold, respectively. Replacing valine at ε codon 265 either by a still smaller glycine or by a larger leucine also lengthens the burst duration. Our analysis reveals that each valine in the valine ring contributes to channel kinetics equally, and the valine ring has been optimized in the course of evolution to govern channel gating.
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota. shen.xinming@mayo.edu, age@mayo.edu.
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Shen
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Okuno
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Margherita
authors.initials: M
authors.lastname: Milone
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Otsuka
authors.affiliation: Department of Child Neurology, National Center Hospital of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Child Neurology, National Center Hospital of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Komaki
authors.affiliation: Child Neurology Solutions, PLLC, St. Paul, Minnesota.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Giles
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota.|Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kinji
authors.initials: K
authors.lastname: Ohno
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Engel
mesh_terms: D019943:Amino Acid Substitution; D002648:Child; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics*; D010375:Pedigree; D000072417:Protein Domains; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014633:Valine / Q000235:genetics*; D055815:Young Adult
chemical_list: C519072:CHRNB1 protein, human; C504423:CHRNE protein, human; D011978:Receptors, Nicotinic; D014633:Valine
keywords: acetylcholine receptors; congenital myasthenic syndrome; ion channel; patch-clamp; slow-channel syndrome