Usher syndrome type I (USH1) is an autosomal recessive disorder characterized by congenital
sensorineural hearing loss, vestibular dysfunction and
visual impairment due to early onset
retinitis pigmentosa (RP). So far, six loci (USH1A-USH1F) have been mapped, but only two USH1 genes have been identified: MYO7A for USH1B and the gene encoding harmonin for USH1C. We identified a Cuban pedigree linked to the locus for
Usher syndrome type 1D (MIM 601067) within the q2 region of chromosome 10). Affected individuals present with congenital
deafness and a highly variable degree of
retinal degeneration. Using a positional candidate approach, we identified a new member of the
cadherin gene superfamily, CDH23. It encodes a
protein of 3,354
amino acids with a single transmembrane domain and 27
cadherin repeats. In the Cuban family, we detected two different mutations: a severe course of the
retinal disease was observed in individuals homozygous for what is probably a truncating splice-site mutation (c.4488G-->C), whereas mild RP is present in individuals carrying the homozygous missense mutation R1746Q. A variable expression of the
retinal phenotype was seen in patients with a combination of both mutations. In addition, we identified two mutations, Delta M1281 and IVS51+5G-->A, in a German USH1 patient. Our data show that different mutations in CDH23 result in USH1D with a variable
retinal phenotype. In an accompanying paper, it is shown that mutations in the mouse ortholog cause disorganization of inner ear stereocilia and
deafness in the waltzer mouse.