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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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.
Pedigrees of DFNB59 families 700 and 710.
Phylogenetic tree shwoing the evolutionary relationships between pejvakin and the remaining members of the DFNA5-gasdermin-MLZE protein family.
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.
Expression of pejvakin in the murine organ of Corti.
Examples of ABR waveforms in response to 20-kHz tone bursts at 80 dB SPL.
Strategy for targeted replacement of the wild-type Dfnb59 allele with Dfnb59 tm1 Ugds
Sequences of primers used to amplify DFNB59 exons.