| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 13q34 | ?Auditory neuropathy, autosomal dominant 2 | 620384 | Autosomal dominant | 3 | ATP11A | 605868 |
A number sign (#) is used with this entry because of evidence that autosomal dominant auditory neuropathy-2 (AUNA2) is caused by heterozygous mutation in the ATP11A gene (605868) on chromosome 13q34. One such family has been reported.
Autosomal dominant auditory neuropathy-2 (AUNA2) is characterized by postlingual onset of progressive bilateral sensorineural hearing loss in the second decade, leading to profound deafness in the fifth decade. Affected individuals show abnormal auditory brainstem responses (ABR) even before the onset of symptoms. Outer hair cell (OHC) function is preserved initially, but declines with age (Lang-Roth et al., 2017).
For a discussion of genetic heterogeneity of autosomal dominant auditory neuropathy, see AUNA1 (609129).
Lang-Roth et al. (2017) reported a large 4-generation German family in which 11 members had progressive bilateral sensorineural hearing loss due to auditory neuropathy. Onset of hearing loss with poor speech discrimination occurred in the second decade, with progression to profound hearing loss in the fifth decade. Auditory brainstem responses were abnormal as early as the first decade, whereas transient-evoked otoacoustic emissions (TEOAE) were normal at onset but declined with age, suggesting secondary loss of outer hair cell function. Stapedial reflexes were absent. Hearing aids compensated mild to moderate hearing loss but did not provide as much help as anticipated.
The transmission pattern of AUNA2 in the family reported by Lang-Roth et al. (2017) was consistent with autosomal dominant inheritance.
By genomewide linkage analysis in a large German family with auditory neuropathy, Lang-Roth et al. (2017) identified 2 regions on chromosomes 12q24 and 13q24 that were candidates for AUNA2. The authors noted that the locus for AUNA2 overlaps with that of DFNA33 (614211), but that DFNA33 is classified as cochlear hearing loss with missing TEOAE, which may be a different disorder.
In 10 affected individuals spanning 3 generations of a large German family with AUNA2, previously reported by Lang-Roth et al. (2017), Chepurwar et al. (2023) identified a heterozygous 5,500-bp deletion encompassing the last coding exon (exon 29) of the ATP11A gene (605868.0004). The deletion, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the mutant protein localized normally to the plasma membrane but had reduced flippase activity for phosphatidylserine compared to wildtype isoform 1. Chepurwar et al. (2023) noted that heterozygous mutations in the ATP11A gene have also been found in patients with DFNA84 (619810), but it was unknown from the phenotyping whether those patients had auditory neuropathy.
Chepurwar, S., von Loh, S. M., Wigger, D. C., Neef, J., Frommolt, P., Beutner, D., Lang-Roth, R., Kubisch, C., Strenzke, N., Volk, A. E. A mutation in ATP11A causes autosomal-dominant auditory neuropathy type 2. Hum. Molec. Genet. 32: 1083-1089, 2023. [PubMed: 36300302] [Full Text: https://doi.org/10.1093/hmg/ddac267]
Lang-Roth, R., Fischer-Krall, E., Kornblum, C., Nurnberg, G., Meschede, D., Goebel, I., Nurnberg, P., Beutner, D., Kubisch, C., Walger, M., Volk, A. E. AUNA2: a novel type of non-syndromic slowly progressive auditory synaptopathy/auditory neuropathy with autosomal-dominant inheritance. Audiol. Neurootol. 22: 30-40, 2017. [PubMed: 28601886] [Full Text: https://doi.org/10.1159/000474929]