Usher Syndrome 1D and Nonsyndromic Autosomal Recessive Deafness DFNB12 Are Caused by Allelic Mutations of the Novel Cadherin-Like Gene CDH23

Abstract

Genes causing nonsyndromic autosomal recessive deafness (DFNB12) and deafness associated with retinitis pigmentosa and vestibular dysfunction (USH1D) were previously mapped to overlapping regions of chromosome 10q21-q22. Seven highly consanguineous families segregating nonsyndromic autosomal recessive deafness were analyzed to refine the DFNB12 locus. In a single family, a critical region was defined between D10S1694 and D10S1737, approximately 0.55 cM apart. Eighteen candidate genes in the region were sequenced. Mutations in a novel cadherin-like gene, CDH23, were found both in families with DFNB12 and in families with USH1D. Six missense mutations were found in five families with DFNB12, and two nonsense and two frameshift mutations were found in four families with USH1D. A northern blot analysis of CDH23 showed a 9.5-kb transcript expressed primarily in the retina. CDH23 is also expressed in the cochlea, as is demonstrated by polymerase chain reaction amplification from cochlear cDNA.

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).…”

“…Patients with USH1 are congenitally deaf, have vestibular dysfunction, and develop retinitis pigmentosa (Smith et al 1994). Both genes have also been shown to underlie nonsyndromic forms of deafness (Liu et al 1997a,b;Weil et al 1997;Bork et al 2001). Recently, Myo7a and Cdh23 were both shown to bind to harmonin suggesting that these molecules form a functional complex within the stereocilia (Boeda et al 2002).…”

An ENU-Induced Mutation of Cdh23 Causes Congenital Hearing Loss, but No Vestibular Dysfunction, in Mice

“…CDH23-null mutations appear to cause USH1D, whereas missense mutations cause nonsyndromic deafness. 2 Most mice with Cdh23 mutations present with the waltzer phenotype: hearing loss and vestibular dysfunction. 9 -13 However, in mice, mutations in Cdh23 have not been associated with retinal degeneration.…”

“…DFNB12 deafness is usually caused by missense mutations in CDH23 alleles and USH1D by null mutations. [2][3][4][5][6][7] A synonymous single-nucleotide polymorphism, Cdh23 753A , is linked to age-related hearing loss in mice. 8 Null mutations in mouse Cdh23 lead to the waltzer phenotype, characterized by hearing loss and vestibular dysfunction.…”

Listen to your gut: Using adhesion to shape the surface of functionally diverse epithelia

“…[40][41][42][43][44][45] Molecular mechanisms underpinning the various forms of Usher Syndrome have been the focus of extensive investigations for many years, and insights offered by these studies have illuminated our understanding of the mechanotransduction process. 46 Whereas most tip-link and IMAC components are expressed from different genes, USH1C represents the only component common to both complexes.…”