Abstract
Usher syndrome type 1 (USH1) is an autosomal recessive sensory defect involving congenital profound sensorineural deafness, vestibular dysfunction and blindness (due to progressive retinitis pigmentosa)1. Six different USH1 loci have been reported. So far, only MYO7A (USH1B), encoding myosin VIIA (ref. 2), has been identified as a gene whose mutation causes the disease. Here, we report a gene underlying USH1C (MIM 276904), a USH1 subtype described in a population of Acadian descendants from Louisiana3 and in a Lebanese family4. We identified this gene (USH1C), encoding a PDZ-domain–containing protein, harmonin, in a subtracted mouse cDNA library derived from inner ear sensory areas. In patients we found a splice-site mutation, a frameshift mutation and the expansion of an intronic variable number of tandem repeat (VNTR). We showed that, in the mouse inner ear, only the sensory hair cells express harmonin. The inner ear Ush1c transcripts predicted several harmonin isoforms, some containing an additional coiled-coil domain and a proline- and serine-rich region. As several of these transcripts were absent from the eye, we propose that USH1C also underlies the DFNB18 form of isolated deafness.
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Acknowledgements
We thank J. Loiselet for collaboration; S. Bundey, M. Batzer, M. DeAngelis, P. Deininger, J. Doucet, M. Pelias and S. Savas for clinical and genetic analysis of Usher patients; J.-P. Hardelin and S. Safieddine for critical reading of the manuscript; M. Grati, B. Boeda and M. Cohen-Salmon for providing us with mouse RNA; M. Mustapha and L. Gresh for advice; and S. Chardenoux and O. Ardouin for aid with figure drawing. This work was supported by grants from the European Economic Community (QLG2-CT-1999-00988), Retina France, Fondation pour la Recherche Médicale, König Forschung contra Blindheit Initiative Usher Syndrome, CEDRE funds (968/R), the Foundation Fighting Blindness, the Deafness Research Foundation NIHR01 DC02530, and NIDCD R03 DC04530, and by C. and J.-P. Bernais donation.
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Verpy, E., Leibovici, M., Zwaenepoel, I. et al. A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C. Nat Genet 26, 51–55 (2000). https://doi.org/10.1038/79171
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DOI: https://doi.org/10.1038/79171
