title: Molecular mechanism of rigid spine with muscular dystrophy type 1 caused by novel mutations of selenoprotein N gene.
abstract: Mutations of selenoprotein N, 1 gene (SEPN1) cause rigid spine with muscular dystrophy type 1 (RSMD1), multiminicore disease, and desmin-related myopathy. We found two novel SEPN1 mutations in two Japanese patients with RSMD1. To clarify the pathomechanism of RSMD1, we performed immunohistochemical studies using a newly developed antibody for selenoprotein N. Selenoprotein N was diffusely distributed in the cytoplasm of the control muscle, but was reduced and irregularly expressed in the cytoplasm of a patient with RSMD1. The expression pattern was very similar to that of calnexin, a transmembrane protein of the endoplasmic reticulum. Selenoprotein N seems to be an endoplasmic reticulum glycoprotein, and loss of this protein leads to disturbance of muscular function. One of the families had the SEPN1 homozygous mutation in the initiation codon 1_2 ins T in exon 1 and showed truncated protein expression. The other had a homozygous 20-base duplication mutation at 80 (80_99dup, frameshift at R27) which, in theory, should generate many nonsense mutations including TGA. These nonsense mutations are premature translation termination codons and they degrade immediately by the process of nonsense-mediated decay (NMD). However, truncated selenoprotein N was also expressed. A possible mechanism behind this observation is that SEPN1 mRNAs may be resistant to NMD. We report on the possible molecular mechanism behind these mutations in SEPN1. Our study clarifies molecular mechanisms of this muscular disorder.
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University, Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima, 890-8520, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takashima
authors.forename: Itsuro
authors.initials: I
authors.lastname: Higuchi
authors.forename: Wataru
authors.initials: W
authors.lastname: Matsuyama
authors.forename: Masahito
authors.initials: M
authors.lastname: Suehara
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Nishihira
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hashiguchi
authors.forename: Ryuki
authors.initials: R
authors.lastname: Hirano
authors.forename: Arlene R
authors.initials: AR
authors.lastname: Ng
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Shuji
authors.initials: S
authors.lastname: Izumo
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Osame
authors.forename: Kimiyoshi
authors.initials: K
authors.lastname: Arimura
mesh_terms: D000328:Adult; D001483:Base Sequence; D037281:Calnexin / Q000378:metabolism; D002878:Chromosomes, Human, Pair 1; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009132:Muscles / Q000378:metabolism / Q000473:pathology; D009136:Muscular Dystrophies / Q000209:etiology* / Q000235:genetics*; D009154:Mutation; D051140:Selenoproteins / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D009124:Muscle Proteins; C435489:SELENON protein, human; D051140:Selenoproteins; D037281:Calnexin