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.
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Acknowledgements
We thank the families described for their cooperation. We also thank Ms. S. Taniguchi and N. Hirata of Kagoshima University for their excellent technical assistance. This study was supported in part by grants from the Muscular dystrophy and Neuropathy of the Ministry of Health and Welfare of Japan to Y. O., H.T., I. H., M.S., M.O., and K.A., from the Kato foundation, Kanae Foundation and the Nakabayashi Trust for ALS research to H.T., and Scientific Research grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan to M.N., H.T., I.H. W.M., and K.A.
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Accession numbers and URLs for data in this article are as follows:
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Online Mendelian Inheritance in Man (OMIM): http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? db=OMIM (for SEPN1 [MIM *606210], LMNA [MIM *150330],)
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GenBank: http://www.ncbi.nih.gov/Genbank (for human SEPN1 mRNA sequence [NM_020451], LMNA mRNA sequence [NM_170707])
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Primer v3 program, Whitehead Institute for Biomedical Research: http://frodo.wi.mit.edu/cgi-bin/primer3/primer3_www.cgi
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Okamoto, Y., Takashima, H., Higuchi, I. et al. Molecular mechanism of rigid spine with muscular dystrophy type 1 caused by novel mutations of selenoprotein N gene. Neurogenetics 7, 175–183 (2006). https://doi.org/10.1007/s10048-006-0046-0
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DOI: https://doi.org/10.1007/s10048-006-0046-0