title: Congenital myasthenic syndrome in Japan: ethnically unique mutations in muscle nicotinic acetylcholine receptor subunits.
abstract: Congenital myasthenic syndromes (CMS) are caused by mutations in genes expressed at the neuromuscular junction. Most CMS patients have been reported in Western and Middle Eastern countries, and only four patients with COLQ mutations have been reported in Japan. We here report six mutations in acetylcholine receptor (AChR) subunit genes in five Japanese patients. Five mutations are novel, and one mutation is shared with a European American patient but with a different haplotype. Among the observed mutations, p.Thr284Pro (p.Thr264Pro according to the legacy annotation) in the epsilon subunit causes a slow-channel CMS. Five other mutations in the delta and epsilon subunits are splice site, frameshift, null, or missense mutations causing endplate AChR deficiency. We also found a heteroallelic p.Met465Thr in the beta subunit in another patient. p.Met465Thr, however, was likely to be polymorphism, because single channel recordings showed mild shortening of channel openings without affecting cell surface expression of AChR, and the minor allelic frequency of p.Met465Thr was 5.1% in the Japanese population. Lack of shared mutant alleles between the Japanese and the other patients suggests that most mutations described here are ethnically unique or de novo in each family.
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Azuma
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Nakata
authors.affiliation: Department of Physiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Motoki
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
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: Mikako
authors.initials: M
authors.lastname: Ito
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Iwata
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: Segawa Neurological Clinic for Children, Tokyo, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Nomura
authors.affiliation: Department of Pediatrics, Nagoya City University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ando
authors.affiliation: Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Ishigaki
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Bisei
authors.initials: B
authors.lastname: Ohkawara
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Masuda
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Natsume
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Kojima
authors.affiliation: Department of Physiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sokabe
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: ohnok@med.nagoya-u.ac.jp.
authors.forename: Kinji
authors.initials: K
authors.lastname: Ohno
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007564:Japan / Q000208:ethnology; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000208:ethnology* / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D021122:Protein Subunits / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000502:physiology; D055815:Young Adult
chemical_list: D021122:Protein Subunits; D011978:Receptors, Nicotinic
keywords: Acetylcholine receptor; Congenital myasthenic syndromes; Endplate acetylcholine receptor deficiency; Fast channel syndrome; Slow channel syndrome