Mutations in the alternatively spliced exons of USH1C cause non-syndromic recessive deafness

We have recently shown that USHIC underlies Usher syndrome type 1c (USHIC), an USH1 subtype characterized by profound deafness, retinitis pigmentosa, and vestibular dysfunction. USHIC encodes a PDZ-domain-containing protein, harmonin. Eight different Ush1c transcripts were identified in the mouse inner ear. Moreover, transcripts containing seven alternatively spliced exons (A-F, G/G) were found to be expressed in the inner ear, but not in the eye. These findings suggested that mutations involving USHIC might also be the cause of DFNB18, a form of non-syndromic deafness, which maps to a chromosomal region that includes USHIC. We screened 32 Chinese multiplex families with non-syndromic recessive deafness for USHIC mutations. In one family, congenital profound deafness without RP was associated with a C to G transversion in the alternatively spliced exon D, predicting an arginine to proline substitution at codon 608 in the proline-, serine- and threonine-rich region of harmonin. We also screened 320 deaf probands from other ethnic background and found three who were heterozygous for changes in the alternately spliced exons including Gly431Val in exon B, Arg620Leu and Arg636Cys in exon D. None of these mutations were detected in DNA from 200 control subjects with normal hearing including I 10 Chinese. We also screened 121 non-Acadian probands with type 1 Usher syndrome. None carried any mutations in these exons of USHIC. Our findings show that USHIC mutations can also cause non-syndromic deafness and that some harmonin isoforms are specifically required for inner ear function.