DO: 0112373;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p25.1 | Auditory neuropathy, autosomal dominant 3 | 619832 | Autosomal dominant | 3 | TMEM43 | 612048 |
A number sign (#) is used with this entry because of evidence that autosomal dominant auditory neuropathy-3 (AUNA3) is caused by heterozygous mutation in TMEM43 gene (612048) on chromosome 3p25.
Autosomal dominant auditory neuropathy-3 (AUNA3) is characterized by progressive hearing loss with inability to discriminate speech but preserved sensitivity to sound (Jang et al., 2021).
For a discussion of genetic heterogeneity of autosomal dominant auditory neuropathy, see AUNA1 (609129).
Jang et al. (2021) reported 15 individuals from 2 unrelated families with autosomal dominant auditory neuropathy. In 4 affected individuals (patients 17, 291, 284 and 304), audiologic findings included elevated pure-tone audiogram (PTA) thresholds with disproportionately lower speech discrimination scores. These patients had classic signs of auditory neuropathy, including absent auditory brainstem response despite the presence of distortion-product otoacoustic emissions or cochlear microphonics. PTA thresholds were measured serially in 3 individuals (patients 284, 374 and 376), which demonstrated a time-dependent progression of hearing loss. In one of these 3 individuals (patient 284), hearing loss significantly worsened after 15 years of age. In the other 2 (patients 374 and 376), elevation of low frequency PTA thresholds began from the age of 10 years.
The transmission pattern of auditory neuropathy-3 in the family reported by Jang et al. (2021) was consistent with autosomal dominant inheritance.
Jang et al. (2021) performed cochlear implants in 3 patients with AUNA3, which restored the ability to discriminate speech.
In 5 members in 3 generations of a Han Chinese family (HN66) and 10 members in 4 generations of a Korean family (SB162) with AUNA3, Jang et al. (2021) identified a heterozygous nonsense mutation (R372X; 612048.0005) in the TMEM43 gene. The mutation was identified by a combination of linkage analysis, whole-exome sequencing, and Sanger sequencing.
Jang et al. (2021) found that mouse models heterozygous or homozygous for an R372X mutation (612048.0005) in the Tmem43 gene demonstrated progressive hearing loss and abnormal passive conductance current from glia-like supporting cells (GLSs) in the organ of Corti of the inner ear. On microscopic examination, apical surfaces of the GLSs at the inner border of the organ of Corti from mice with the heterozygous R372X mutation were narrower compared to wildtype mice starting at 7 months of age.
Jang, M. W., Oh, D.-Y., Yi, E., Liu, X., Ling, J., Kim, N., Sharma, K., Kim, T. Y., Lee, S., Kim, A.-R., Kim, M. Y., Kim, M., and 32 others. A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder. Proc. Nat. Acad. Sci. 118: e2019681118, 2021. [PubMed: 34050020] [Full Text: https://doi.org/10.1073/pnas.2019681118]