Auditory Neuropathy, Autosomal Dominant, 1

A number sign (#) is used with this entry because autosomal dominant auditory neuropathy-1 (AUNA1) is caused by heterozygous mutation in the DIAPH3 gene (614567) on chromosome 13q.

Description

Auditory neuropathy is a type of hearing loss defined by the preservation of cochlear outer hair cell function and abnormal or absent auditory brainstem responses. Auditory neuropathy may accompany peripheral neuropathy in a variety of dominant syndromes such as Charcot-Marie-Tooth disease (Satya-Murti et al., 1979) and has been observed in Friedreich ataxia (Satya-Murti et al., 1980). Auditory neuropathy unassociated with peripheral neuropathy most commonly occurs as a sporadic or recessive trait; see, for example, 601071.

Clinical Features

Kim et al. (2004) described a multigenerational U.S. family of European descent segregating autosomal dominant auditory neuropathy. Hearing loss had an average age of onset of 18.6 years. Affected members were heterozygous except for 2 homozygous individuals whose parents were consanguineous. However, with the exception of an age of onset at the lower end of the range (8 and 9 years), there were no apparent clinical features differentiating their phenotype from that of the heterozygotes. Kim et al. (2004) predicted that the mutation in this family will be found to be noninactivating, e.g., a missense mutation rather than a null mutation resulting in haploinsufficiency. In the latter case, the complete lack of functional protein in the homozygotes would be expected to result in a more severe phenotype.

In the family reported by Kim et al. (2004), Starr et al. (2004) found a marked improvement of auditory functions in 3 affected family members after cochlear implantation. The patients had a return of electrically evoked auditory brainstem responses (EABRs), auditory temporal processes, and speech recognition. The findings were compatible with a distal auditory nerve disorder affecting 1 or all of the components in the auditory periphery including terminal auditory nerve dendrites, inner hair cells, and the synapses between inner hair cells and the auditory nerve.

Mapping

In a multigenerational US family of European descent segregating autosomal dominant auditory neuropathy, Kim et al. (2004) mapped the disorder to a locus on 13q14-q21 between markers D13S153 and D13S1317 (maximum 2-point lod score of 9.87 at theta = 0.019 for D13S153).

Molecular Genetics

In affected members of a family with autosomal dominant auditory neuropathy-1 originally reported by Kim et al. (2004), Schoen et al. (2010) identified a heterozygous mutation (-172G-A; 614567.0001) in the 5-prime untranslated region of the DIAPH3 gene that resulted in increased mRNA and protein expression. Drosophila with constitutive overexpression of a mutant Diaph gene in the auditory organ had reduced sound-evoked potentials. The findings indicated that AUNA1 is caused by overexpression of the DIAPH3 gene due to a mutation in a transcriptional regulatory site, consistent with a gain of function.