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Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy

Nature Genetics volume 38, pages 770778 (2006) | Download Citation

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Abstract

Auditory neuropathy is a particular type of hearing impairment in which neural transmission of the auditory signal is impaired, while cochlear outer hair cells remain functional. Here we report on DFNB59, a newly identified gene on chromosome 2q31.1–q31.3 mutated in four families segregating autosomal recessive auditory neuropathy. DFNB59 encodes pejvakin, a 352-residue protein. Pejvakin is a paralog of DFNA5, a protein of unknown function also involved in deafness. By immunohistofluorescence, pejvakin is detected in the cell bodies of neurons of the afferent auditory pathway. Furthermore, Dfnb59 knock-in mice, homozygous for the R183W variant identified in one DFNB59 family, show abnormal auditory brainstem responses indicative of neuronal dysfunction along the auditory pathway. Unlike previously described sensorineural deafness genes, all of which underlie cochlear cell pathologies, DFNB59 is the first human gene implicated in nonsyndromic deafness due to a neuronal defect.

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Acknowledgements

The authors are grateful to all the families and clinicians involved in the study for their collaboration. We thank the staff at the Pasteur Institute of Iran and the Specialized Education Centers for their help in collecting subject samples; T. Hutchin and R.F. Mueller for generously sharing DNA samples from individuals belonging to the family that defined the DFNB27 locus; N.G. Copeland for gifts of bacterial strains and plasmids; S. Nouaille, S. Chardenoux and F. Thouron for technical help; P. Roux for advice on confocal microscopy; M. Cohen-Salmon and S. Safieddine for advice on immunohistofluorescence techniques; J. Levilliers and A. Hafidi for discussion and J.P. Hardelin for critical reading of the manuscript. S.D. is grateful for the support of the Letten Saugstad Foundation. F.J.d.C was a recipient of a Marie Curie postdoctoral fellowship. L.V.L. is a postdoctoral fellow of the Flemish Fonds voor Wetenschappelijk Onderzoek (FWO). This work was supported by the European Commission FP6 Integrated Project EuroHear (LSHG-CT-2004-512063) and by Fondation Louis-Jeantet.

Author information

Affiliations

  1. Unité de Génétique des Déficits Sensoriels INSERM U587, Institut Pasteur, 25, rue du Docteur Roux, 75724 Paris Cedex 15, France.

    • Sedigheh Delmaghani
    • , Francisco J del Castillo
    • , Vincent Michel
    • , Michel Leibovici
    • , Asadollah Aghaie
    • , Dominique Weil
    •  & Christine Petit
  2. Department of Biochemistry, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel Aviv, Israel.

    • Uri Ron
    •  & Nir Ben-Tal
  3. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.

    • Lut Van Laer
    •  & Guy Van Camp
  4. Centre d'Ingénierie Génétique Murine, Institut Pasteur, Paris, France.

    • Francina Langa
  5. Centre National de Génotypage, Evry, France.

    • Mark Lathrop
  6. Laboratoire de Biophysique Sensorielle, Faculté de Médecine, Université d'Auvergne, Clermont-Ferrand, France.

    • Paul Avan

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Christine Petit.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Pedigrees of DFNB59 families 700 and 710.

  2. 2.

    Supplementary Fig. 2

    Phylogenetic tree shwoing the evolutionary relationships between pejvakin and the remaining members of the DFNA5-gasdermin-MLZE protein family.

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    Supplementary Fig. 3

    Scanning electron micrographs of IHCs and OHCs at equivalent positions in the medial part of the cochlear duct of P30 Dfnb59 +/+ and Dfnb59 tm1 Ugds/tm1 Ugds mice.

  4. 4.

    Supplementary Fig. 4

    Expression of pejvakin in the murine organ of Corti.

  5. 5.

    Supplementary Fig. 5

    Examples of ABR waveforms in response to 20-kHz tone bursts at 80 dB SPL.

  6. 6.

    Supplementary Fig. 6

    Strategy for targeted replacement of the wild-type Dfnb59 allele with Dfnb59 tm1 Ugds

  7. 7.

    Supplementary Table 1

    Sequences of primers used to amplify DFNB59 exons.

  8. 8.

    Supplementary Note

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DOI

https://doi.org/10.1038/ng1829

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