Deafness, Autosomal Recessive 12

A number sign (#) is used with this entry because of evidence that nonsyndromic autosomal recessive deafness-12 (DFNB12) is caused by homozygous or compound heterozygous mutation in the cadherin-23 gene (CDH23; 605516) on chromosome 10q22.

There is also evidence that a mutation in the ATP2B2 gene (108733.0001) modifies the severity of sensorineural hearing loss.

Mutation in the CDH23 gene can also cause the more severe Usher syndrome 1D (USH1D; 601067).

Clinical Features

Chaib et al. (1996) described a consanguineous Sunni family with profound prelingual sensorineural hearing impairment living in an isolated village in Syria.

Wagatsuma et al. (2007) reported 5 unrelated Japanese families with DFNB12. All patients had a similar phenotype, with moderate to profound high-frequency progressive sensorineural hearing loss. The average hearing loss was 84.0 dB. Vestibular function was normal.

Inheritance

The transmission pattern of nonsyndromic deafness in the family reported by Chaib et al. (1996) was consistent with autosomal recessive inheritance.

Chaib et al. (1996) stated that about 75% of the inherited forms of congenital isolated deafness have an autosomal recessive mode of transmission.

Population Genetics

Chaib et al. (1996) noted that deafness affects 1 in 1,000 children in the U.S. at birth or during infancy.

Mapping

By genomewide linkage analysis followed by homozygosity mapping of a Sunni family with sensorineural hearing loss, Chaib et al. (1996) identified a candidate disease locus, designated DFNB12, to chromosome 10q21-q22 (a lod score of 6.40 was obtained with marker D10S535). Analysis of adjacent markers placed the gene distal to D10S529 and proximal to D10S532 in a 11- to 15-cM region. The authors noted that the homologous murine region for DFNB12 contains 3 deaf mouse mutants, including Jackson circler (jc), Waltzer (v), and Ames Waltzer (av).

Molecular Genetics

Bork et al. (2001) demonstrated that DFNB12 is caused by mutations in the CDH23 gene (see, e.g., 605516.0005; 605516.0006).

Wagatsuma et al. (2007) identified 4 different missense mutations in the CDH23 gene (see, e.g., 605516.0014 and 605516.0015) in 6 Japanese patients from 5 families with autosomal recessive hearing loss. All 4 mutations were found in the extracellular domain of the protein. The findings indicated that mutations in the CDH23 gene may account for about 5% of nonsyndromic hearing loss in the Japanese population.

Genotype/Phenotype Correlations

Nonsyndromic DFNB12 deafness is associated with CDH23 missense mutations that are presumed to be hypomorphic alleles with sufficient residual activity for retinal and vestibular function, but not for auditory cochlear function. In contrast, homozygous nonsense, frameshift, splice site and some missense mutations of CDH23, or a combination of these USH1D alleles in a compound heterozygote, cause USH1D. Schultz et al. (2011) identified 12 different homozygous CDH23 missense mutations, including 8 novel mutations, in 13 families with DFNB12. All were missense, except 1 in-frame deletion. Ten different homozygous mutations were found in 14 families and 1 singleton with USH1D. These latter mutations were mostly nonsense, frameshift, or splice site mutations, but there was 1 in-frame deletion and 2 missense mutations. Affected individuals in 3 additional families were found to carry compound heterozygous mutations in the CDH23 gene, with the different alleles being associated with either DFNB12 or USH1D. Based on the phenotypes within families, the results indicated that USH1D occurs only when there are 2 USH1D alleles in trans. In contrast, when there is a DFNB12 allele in trans with a USH1D allele, the phenotype is DFNB12. The findings indicated that a DFNB12 allele is phenotypically dominant to a USH1D allele, and can preserve normal retinal and vestibular function even in the presence of a USH1D allele. Schultz et al. (2011) noted the implications for genetic counseling.

Animal Model

In an N-ethyl-N-nitrosourea (ENU) mutagenesis screen, Schwander et al. (2009) identified 'salsa' mice, which suffer from progressive hearing loss and carry a Cdh23 mutation (E737V) that is predicted to affect Ca(2+) binding by the extracellular domain. Otoacoustic emissions were not detected, suggesting a defect in outer hair cell function. Similar mutations in the human CDH23 gene cause DFNB12. Although hair bundle development appeared unaffected in salsa mice, tip links were progressively lost, resulting in hair cell death. Tip links in vestibular hair cells were unaffected. Biochemical studies showed that mutant Cdh23 had impaired interaction with Pcdh15. The findings suggested that missense mutations in DFNB12 patients lead to deafness by affecting tip links.