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Gentamicin-induced readthrough and nonsense-mediated mRNA decay of SERPINB7 nonsense mutant transcripts

Gentamicin-induced readthrough and nonsense-mediated mRNA decay of SERPINB7 nonsense mutant transcripts

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Authors

  • Yuka Ohguchi
  • Toshifumi Nomura (Lead / Corresponding author)
  • Shotaro Suzuki
  • Masae Takeda
  • Toshinari Miyauchi
  • Osamu Mizuno
  • Satoru Shinkuma
  • Yasuyuki Fujita
  • Osamu Nemoto
  • Kota Ono
  • W. H. Irwin McLean
  • Hiroshi Shimizu (Lead / Corresponding author)

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Info

Original languageEnglish
Pages (from-to)836-843
Number of pages8
JournalJournal of Investigative Dermatology
Volume138
Issue number4
Early online date26 Oct 2017
DOIs
StatePublished - Apr 2018

Abstract

Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive skin disorder with a high, unmet medical need that is caused by mutations in SERPINB7. Almost all NPPK patients carry the founder nonsense mutation c.796C>T (p.Arg266Ter) in the last exon of SERPINB7. Here we sought to determine whether topical "nonsense-suppression (readthrough)" therapy using gentamicin is applicable to NPPK. First, we demonstrated that gentamicin enhanced readthrough activity in cells transfected with SERPINB7 cDNA carrying the mutation and promoted full-length SERPINB7 protein synthesis in NPPK keratinocytes. We next conducted an investigator-blinded, randomized, bilaterally controlled compassionate use study of topical gentamicin in which five NPPK patients with c.796C>T were enrolled. Patients' selfreported improvement of hyperkeratosis was significantly greater on the gentamicin side than the control side (P=0.0349). In two patients, hyperkeratosis was improved on the gentamicin side, as determined by a blinded-investigator assessment. These results indicate the therapeutic potential of topical gentamicin for NPPK. Unexpectedly, we also found that mutant SERPINB7 mRNAs harboring r.796c>u were degraded by nonsense-mediated mRNA decay. Furthermore, the truncated SERPINB7 protein was degraded via a proteasome-mediated pathway. These findings provide important insights into the mRNA/protein quality control system in humans, which could be a potential therapeutic target for genetic diseases. (199 words).

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