A mutation in the SEPN1 selenocysteine redefinition element (SRE) reduces selenocysteine incorporation and leads to SEPN1-related myopathy

Baijayanta Maiti, Sandrine Arbogast, Valérie Allamand, Mark W. Moyle, Christine B. Anderson, Pascale Richard, Pascale Guicheney, Ana Ferreiro, Kevin M. Flanigan, Michael T. Howard

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Mutations in SEPN1 result in a spectrum of early-onset muscle disorders referred to as SEPN1-related myopathy. The SEPN1 gene encodes selenoprotein N (SelN), which contains the amino acid selenocysteine (Sec). Incorporation of Sec occurs due to redefinition of a UGA codon during translation. Efficient insertion requires a Sec insertion sequence (SECIS) in the 3′UTR and, for at least a subset of selenoprotein genes, a Sec redefinition element (SRE) located adjacent to the UGA codon. We report the effect of three novel and one previously reported point mutation in the SelN SRE element on Sec insertion efficiency. Notably, the previously reported mutation c.1397G> A (p.R466Q), which weakens the secondary structure of the SRE element, reduces Sec insertion efficiency and SelN RNA levels. Muscle from patients with this mutation have negligible levels of SelN protein. This data highlights the importance of the SRE element during SelN expression and illustrates a novel molecular mechanism by which point mutations may lead to SEPN1-related myopathy.

Original languageEnglish
Pages (from-to)411-416
Number of pages6
JournalHuman mutation
Volume30
Issue number3
DOIs
StatePublished - Mar 1 2009
Externally publishedYes

Keywords

  • Myopathy
  • Recoding
  • SEPN1
  • SelN
  • Selenium
  • Selenocysteine
  • Selenoprotein N

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    Maiti, B., Arbogast, S., Allamand, V., Moyle, M. W., Anderson, C. B., Richard, P., Guicheney, P., Ferreiro, A., Flanigan, K. M., & Howard, M. T. (2009). A mutation in the SEPN1 selenocysteine redefinition element (SRE) reduces selenocysteine incorporation and leads to SEPN1-related myopathy. Human mutation, 30(3), 411-416. https://doi.org/10.1002/humu.20879