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). 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
Louisiana and in a Lebanese family. 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.
