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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 770–778 (2006)Cite this article

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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Figure 1: Mapping the DFNB59 locus.
Figure 2: Audiological characterization of affected individuals with mutations in the DFNB59 gene.
Figure 3: Genomic structure of DFNB59.
Figure 4: CONSEQ conservation analysis of human pejvakin based on the alignment of the 53 full-length members of the pejvakin-DFNA5-gasdermin-MLZE family known to date.
Figure 5: Audiological characterization of postnatal day 30 Dfnb59 knock-in mice.
Figure 6: Expression of pejvakin in the afferent auditory system of P30 mice from pure 129/Sv genetic background.

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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.

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Authors and Affiliations

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

Supplementary Fig. 1

Pedigrees of DFNB59 families 700 and 710. (PDF 116 kb)

Supplementary Fig. 2

Phylogenetic tree shwoing the evolutionary relationships between pejvakin and the remaining members of the DFNA5-gasdermin-MLZE protein family. (PDF 251 kb)

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 Dfnb59tm1 Ugds/tm1 Ugds mice. (PDF 405 kb)

Supplementary Fig. 4

Expression of pejvakin in the murine organ of Corti. (PDF 135 kb)

Supplementary Fig. 5

Examples of ABR waveforms in response to 20-kHz tone bursts at 80 dB SPL. (PDF 111 kb)

Supplementary Fig. 6

Strategy for targeted replacement of the wild-type Dfnb59 allele with Dfnb59tm1 Ugds (PDF 90 kb)

Supplementary Table 1

Sequences of primers used to amplify DFNB59 exons. (PDF 102 kb)

Supplementary Note (PDF 104 kb)

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Delmaghani, S., del Castillo, F., Michel, V. et al. Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy. Nat Genet 38, 770–778 (2006). https://doi.org/10.1038/ng1829

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