Human Genetics

, Volume 122, Issue 3–4, pp 373–381 | Cite as

In vitro and ex vivo suppression by aminoglycosides of PCDH15 nonsense mutations underlying type 1 Usher syndrome

  • Annie Rebibo-Sabbah
  • Igor Nudelman
  • Zubair M. Ahmed
  • Timor Baasov
  • Tamar Ben-Yosef
Original Investigation

Abstract

Type 1 Usher syndrome (USH1) is a recessively inherited condition, characterized by profound prelingual deafness, vestibular areflexia, and prepubertal onset of retinitis pigmentosa (RP). While the auditory component of USH1 can be treated by cochlear implants, to date there is no effective treatment for RP. USH1 can be caused by mutations in each of at least six genes. While truncating mutations of these genes cause USH1, some missense mutations of the same genes cause nonsyndromic deafness. These observations suggest that partial or low level activity of the encoded proteins may be sufficient for normal retinal function, although not for normal hearing. In individuals with USH1 due to nonsense mutations, interventions enabling partial translation of a full-length functional protein may delay the onset and/or progression of RP. One such possible therapeutic approach is suppression of nonsense mutations by small molecules such as aminoglycosides. We decided to test this approach as a potential therapy for RP in USH1 patients due to nonsense mutations. We initially focused on nonsense mutations of the PCDH15 gene, underlying USH1F. Here, we show suppression of several PCDH15 nonsense mutations, both in vitro and ex vivo. Suppression was achieved both by commercial aminoglycosides and by NB30, a new aminoglycoside-derivative developed by us. NB30 has reduced cytotoxicity in comparison to commercial aminoglycosides, and thus may be more efficiently used for therapeutic purposes. The research described here has important implications for the development of targeted interventions that are effective for patients with USH1 caused by various nonsense mutations.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Annie Rebibo-Sabbah
    • 1
  • Igor Nudelman
    • 2
  • Zubair M. Ahmed
    • 3
  • Timor Baasov
    • 2
  • Tamar Ben-Yosef
    • 1
  1. 1.Department of Genetics, The Rappaport Family Institute for Research in the Medical Sciences, Rappaport Faculty of MedicineTechnion-Israel Institute of TechnologyHaifaIsrael
  2. 2.Department of Chemistry and Institute of Catalysis Science and TechnologyTechnion-Israel Institute of TechnologyHaifaIsrael
  3. 3.Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication DisordersNational Institutes of HealthRockvilleUSA

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