Disease relevance of CDH23

• Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D [1].
• Mutations in the calcium-binding motifs of CDH23 and the 35delG mutation in GJB2 cause hearing loss in one family [2].
• CDH23 is the first gene known to cause deafness in the human population to be linked with predisposition to noise-induced hearing loss [3].
• Cdh23 mutations in the mouse are associated with retinal dysfunction but not retinal degeneration [4].
• We show that mice heterozygous for a presumed null allele of Cdh23 ( Cdh23(v)) have low- and high-frequency hearing loss at 5-6 weeks of age, the high-frequency component of which worsens with increasing age [3].

High impact information on CDH23

• Using a positional candidate approach, we identified a new member of the cadherin gene superfamily, CDH23 [1].
• Our data show that different mutations in CDH23 result in USH1D with a variable retinal phenotype [1].
• Mutations in human CDH23 cause Usher syndrome type 1D and thus, establish waltzer as the mouse model for USH1D [5].
• We demonstrate Cdh23 expression in the neurosensory epithelium and show that during early hair-cell differentiation, stereocilia organization is disrupted in v(2J) homozygotes [5].
• Only missense mutations of CDH23 have been observed in families with nonsyndromic deafness, whereas nonsense, frameshift, splice-site, and missense mutations have been identified in families with Usher syndrome [6].

Biological context of CDH23

• In humans, we also have obtained evidence for a digenic inheritance of a USH1 phenotype in three unrelated families with mutations in CDH23 and PCDH15 [7].
• In contrast to CDH23 and PCDH15, where most of the changes are truncating mutations, myosin VIIA has both nonsense and missense mutations [8].
• Haplotype analysis by SNPs within CDH23 suggests common ancestors for each of the mutations [9].
• Mutations in CDH23, a gene that encodes a putative cell-adhesion protein with multiple cadherin-like domains, are responsible for both Usher syndrome and DFNB12 nonsyndromic deafness [6].
• RESULTS: PCDH21 spans 23 kb, consists of 17 exons, and encodes a protein that shows close phylogenetic relationship to cadherin-23 (CDH23), the protein involved in Usher syndrome type 1D [10].

Anatomical context of CDH23

• CDH23 is also expressed in the cochlea, as is demonstrated by polymerase chain reaction amplification from cochlear cDNA [11].
• In the ear, CDH23 and harmonin are expressed in the stereocilia of hair cells, and in the retina within the photoreceptor cell layer [12].
• The left temporal bone of patient 2, classified as Usher syndrome genetic subtype USH1D or USH1F, demonstrated the typical signs of severe cochleosaccular degeneration [13].
• In addition, Cdh23 is expressed in the urticulo-saccular foramen,the ductus reuniens, and Reissner's membrane, suggesting that Cdh23 may also be involved in maintaining the ionic composition of the endolymph [14].
• BUS/Idr mice carrying a mutant waltzer allele (vbus) are characterized by splayed hair bundles in inner ear sensory cells, providing a mouse homolog of USH1D/DFNB12 [15].

Associations of CDH23 with chemical compounds

• In addition, other aspartic and glutamic acid residue substitutions in the highly conserved calcium-binding sites reported to cause DFNB12 are also likely to result in a decreased affinity for calcium [2].
• Two PDZ domains in harmonin interact with two complementary binding surfaces in the CDH23 cytoplasmic domain [12].

Other interactions of CDH23

• Altogether, our data indicate that CDH23 and PCDH15 play an essential long-term role in maintaining the normal organization of the stereocilia bundle [7].
• Recently, a variant of the human ATP2B2 gene was shown to exacerbate hearing loss in individuals homozygous for a CDH23 mutation, similar to the Atp2b2(dfw-2J)-Cdh23(753A/G) interaction affecting hearing in mice [16].
• Mutations in the cadherin 23 gene (CDH23) cause Usher syndrome type 1D in humans, a disease that results in retinitis pigmentosa and deafness [4].
• DFNB9 and DFNB12 [17].

Analytical, diagnostic and therapeutic context of CDH23

• A northern blot analysis of CDH23 showed a 9.5-kb transcript expressed primarily in the retina [11].
• In the present study, a panel of 69 probands with Usher syndrome and 38 probands with recessive nonsyndromic deafness were screened for the presence of mutations in the entire coding region of CDH23, by heteroduplex, single-strand conformation polymorphism, and direct sequence analyses [6].
• Assignment of the canine cadherin related 23 gene (CDH23) to chromosome 4q12-->q13 by fluorescence in situ hybridization and radiation hybrid mapping [18].
• Three mutant alleles of Cdh23 were examined by histology and electroretinography (ERG) [4].

References