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Hypothesis
DFNA5: hearing impairment exon instead of hearing impairment gene?
  1. L Van Laer1,
  2. K Vrijens1,
  3. S Thys1,
  4. V F I Van Tendeloo2,
  5. R J H Smith3,
  6. D R Van Bockstaele2,
  7. J-P Timmermans4,
  8. G Van Camp1
  1. 1Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
  2. 2Laboratory of Experimental Haematology, Faculty of Medicine, University of Antwerp, Antwerp University Hospital, Antwerp, Belgium
  3. 3Molecular Otolaryngology Research Laboratories, University of Iowa, Iowa City, Iowa
  4. 4Laboratory of Cell Biology and Histology, University of Antwerp, Antwerp, Belgium
  1. Correspondence to:
 G Van Camp
 Department of Medical Genetics, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, B-2610 Antwerp, Belgium; Guy.VanCampua.ac.be

Abstract

Background: Three mutations in the DFNA5 gene have been described in three families with autosomal dominant non-syndromic hearing impairment. Although these mutations are different at the genomic DNA level, they all lead to skipping of exon 8 at the mRNA level. We hypothesise that hearing impairment associated with DFNA5 is caused by a highly unusual mechanism, in which skipping of one specific exon leads to disease that is not caused by other mutations in this gene. We hypothesise that this represents a very specific “gain of function” mutation, with the truncated protein exerting a deleterious new function.

Methods: We performed transfection experiments in mammalian cell lines (HEK293T and COS-1) with green fluorescent protein (GFP) tagged wildtype and mutant DFNA5 and analysed cell death with flow cytometry and fluorescence microscopy.

Results: Post-transfection death of HEK293T cells approximately doubled when cells were transfected with mutant DFNA5–GFP compared with wildtype DFNA5–GFP. Cell death was attributed to necrotic events and not to apoptotic events.

Conclusion: The transfection experiments in mammalian cell lines support our hypothesis that the hearing impairment associated with DFNA5 is caused by a “gain of function” mutation and that mutant DFNA5 has a deleterious new function.

https://doi.org/10.1136/jmg.2003.015073

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    Footnotes

    • Conflicts of interest: none declared.

    • Funding: This research was supported in part by a grant of the GSKE (Geneeskundige Stichting Koningin Elisabeth) to GVC and LVL and by a NOI-BOF grant of the University of Antwerp to LVL. This research was performed in the framework of the Interuniversity Attraction Poles programme P5/19 of the Federal Office for Scientific, Technical, and Cultural Affairs, Belgium.