Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D

Abstract

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.

A genome-wide association study for age-related hearing impairment in the Saami

“…IQGAP2 is expressed inside the cochlea 36 and has been implicated in cadherin-mediated cell adhesion. 37 As cadherin-23 (CDH23) plays an important role in the sensory hair cells, 38 and mutations in CDH23 are responsible for syndromic and nonsyndromic autosomal recessive deafness in humans 39,40 and agerelated hearing loss in inbred mouse strains, 41 this warrants further research. Intriguingly, the SNP rs161927 (P-value 0.000149), that ranked eighth for PC1, was positioned immediately downstream from the metabotropic GRM7 gene.…”

Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation

“…The protocadherin LKC is associated with contact inhibition of cell proliferation, and has been suggested as a candidate TSG for colon and liver cancer (Okazaki et al, 2002). Mutations in protocadherin 15 as well as CDH23 have also been implicated in Usher syndrome (Bolz et al, 2001;Di et al, 2001;Siemens et al, 2002), as recently demonstrated in a zebrafish model Sollner et al, 2004).…”

Progressive Hearing Loss and Increased Susceptibility to Noise-Induced Hearing Loss in Mice Carrying a Cdh23 but not a Myo7a Mutation

“…Waltzer and shaker1 mutants both have disorganized stereocilia bundles caused by mutations in cadherin 23 (Cdh23) and myosin VIIa (Myo7a), respectively Self et al 1998;Di Palma et al 2001;Holme and Steel 2002). CDH23 is mutated in Usher's syndrome type 1D (USH1D) and MYO7A in USH1B patients (Weil et al 1995;Bolz et al 2001;Bork et al 2001). Patients with USH1 are congenitally deaf, have vestibular dysfunction, and develop retinitis pigmentosa (Smith et al 1994).…”