Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans

Abstract

Mutations in genes coding for cadherin 23 and protocadherin 15 cause deafness in both mice and humans. Here, we provide evidence that mutations at these two cadherin loci can interact to cause hearing loss in digenic heterozygotes of both species. Using a classical genetic approach, we generated mice that were heterozygous for both Cdh23 and Pcdh15 mutations on a uniform C57BL/6J background. Significant levels of hearing loss were detected in these mice when compared to age-matched single heterozygous animals or normal controls. Cytoarchitectural defects in the cochlea of digenic heterozygotes, including degeneration of the stereocilia and a base-apex loss of hair cells and spiral ganglion cells, were consistent with the observed age-related hearing loss of these mice beginning with the high frequencies. 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. Altogether, our data indicate that CDH23 and PCDH15 play an essential long-term role in maintaining the normal organization of the stereocilia bundle.

Effects of exposing gonadectomized and intact C57BL/6J mice to a high-frequency augmented acoustic environment: Auditory brainstem response thresholds and cytocochleograms

“…Mice of the C57BL/6J (B6), DBA/2J (D2), and other strains exhibit genetic age-related hearing loss (for reviews see Erway et al, 1993Erway et al, , 2001Johnson et al, 1997Johnson et al, , 2000Li and Borg, 1991;Zheng et al, 2005). A series of studies has shown this to be ameliorated by treatment with an augmented acoustic environment (AAE) consisting of 12-hour-nightly exposure to noise bursts of 70 dB SPL (re: 20μPa).…”

Preliminary studies on differential expression of auditory functional genes in the brain after repeated blast exposures

“…Cadherin and protocadherin mutations are reported to be involved in noise-induced hearing loss [13][14][16][17]44]. The altered expression profile of cadherins and protocadherins in different regions of the brain after repeated blast exposures may impair central auditory processing.…”

“…A number of genes and their protein products have been reported to be involved in both age-and noise-related hearing loss [10][11][12][13][14][15]. Cadherin and protocadherin mutations were linked to digenic inheritance of deafness and have specific functional roles in noise-induced hearing loss [13][14][16][17].…”

“…Cadherin and protocadherin mutations were linked to digenic inheritance of deafness and have specific functional roles in noise-induced hearing loss [13][14][16][17]. Other groups of proteins involved in deafness are otoferlin and otoancorin, which are also reported to have major roles in auditory functions, including central auditory processing [18][19][20][21].…”

Novel sequence variants in the TMIE gene in families with autosomal recessive nonsyndromic hearing impairment

“…In another mouse model called circling, the mapped locus also includes the Tmie gene [20,21], and the circling mouse also exhibited hair cell axonal and spiral ganglion degeneration [22]. There is a similar pattern of histologic features in Cdh23+/Pcdh15+ and Ush1C +/+ mice [23,24]; additionally, the CDH23, PCDH15, and USH1C proteins have been identified as stereocilia bundling proteins. However, it is difficult to surmise whether the hair cell and/or spiral ganglion loss in the Tmie mouse mutants were due to primary stereocilia defects or to secondary responses to another type of inner ear malfunction.…”