Okamoto Yuji, Takashima Hiroshi, Higuchi Itsuro, Matsuyama Wataru, Suehara Masahito, Nishihira Yasushi, Hashiguchi Akihiro, Hirano Ryuki, Ng Arlene R, Nakagawa Masanori, Izumo Shuji, Osame Mitsuhiro, Arimura Kimiyoshi
Department of Neurology and Geriatrics, Kagoshima University, Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima, 890-8520, Japan.
Neurogenetics. 2006 Jul;7(3):175-83. doi: 10.1007/s10048-006-0046-0. Epub 2006 Jun 15.
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.
硒蛋白N1基因（SEPN1）突变可导致1型刚性脊柱伴肌营养不良（RSMD1）、多微小核心病和结蛋白相关性肌病。我们在两名日本RSMD1患者中发现了两个新的SEPN1突变。为阐明RSMD1的发病机制，我们使用新开发的针对硒蛋白N的抗体进行了免疫组织化学研究。硒蛋白N在对照肌肉的细胞质中呈弥漫性分布，但在一名RSMD1患者的细胞质中减少且表达不规则。其表达模式与内质网跨膜蛋白钙连接蛋白非常相似。硒蛋白N似乎是一种内质网糖蛋白，该蛋白的缺失会导致肌肉功能紊乱。其中一个家系在外显子1的起始密码子1_2插入T处存在SEPN1纯合突变，并显示出截短蛋白表达。另一个家系在80处有一个20碱基重复突变（80_99dup，R27处移码），理论上该突变应产生许多包括TGA在内的无义突变。这些无义突变是过早的翻译终止密码子，它们会通过无义介导的衰变（NMD）过程立即降解。然而，截短的硒蛋白N也有表达。这一观察结果背后的一个可能机制是SEPN1 mRNA可能对NMD具有抗性。我们报告了SEPN1中这些突变背后可能的分子机制。我们的研究阐明了这种肌肉疾病的分子机制。
