A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder

Genes that are primarily expressed in cochlear glia-like supporting cells (GLSs) have not been clearly associated with progressive deafness. Herein, we present a deafness locus mapped to chromosome 3p25.1 and an auditory neuropathy spectrum disorder (ANSD) gene, TMEM43, mainly expressed in GLSs. We identify p.(Arg372Ter) of TMEM43 by linkage analysis and exome sequencing in two large Asian families segregating ANSD, which is characterized by inability to discriminate speech despite preserved sensitivity to sound. The knock-in mouse with the p.(Arg372Ter) variant recapitulates a progressive hearing loss with histological abnormalities in GLSs. Mechanistically, TMEM43 interacts with the Connexin26 and Connexin30 gap junction channels, disrupting the passive conductance current in GLSs in a dominant-negative fashion when the p.(Arg372Ter) variant is introduced. Based on these mechanistic insights, cochlear implant was performed on three subjects, and speech discrimination was successfully restored. Our study highlights a pathological role of cochlear GLSs by identifying a deafness gene and its causal relationship with ANSD.

Download Full-text

Mutations in TMEM43 cause autosomal dominant auditory neuropathy spectrum disorder via interaction with connexin-mediated passive conductance channels

10.1101/2020.07.27.222323 ◽

2020 ◽

Author(s):

Minwoo Wendy Jang ◽

Doo-Yi Oh ◽

Eunyoung Yi ◽

Xuezhong Liu ◽

Jie Ling ◽

...

Keyword(s):

Auditory Neuropathy ◽

Dominant Negative ◽

Spectrum Disorder ◽

Speech Discrimination ◽

Supporting Cells ◽

Progressive Hearing Loss ◽

Auditory Neuropathy Spectrum Disorder ◽

Gap Junction Channels ◽

Deafness Gene

AbstractGenes that are primarily expressed in cochlear glia-like supporting cells (GLSs) have never been clearly associated with progressive deafness. Herein, we present a novel deafness locus mapped to chromosome 3p25.1 and a new auditory neuropathy spectrum disorder (ANSD) gene TMEM43 mainly expressed in GLSs. We identify p.R372X of TMEM43 by linkage analysis and exome sequencing in two large Asian families. The knock-in (KI) mouse with p.R372X mutation recapitulates a progressive hearing loss with histological abnormalities exclusively in GLSs. Mechanistically, TMEM43 interacts with Cx26 and Cx30 gap junction channels, disrupting the passive conductance current in GLSs in a dominant-negative fashion when the p.R372X mutation is introduced. Based on the mechanistic insights, cochlear implant was performed on two patients and speech discrimination was successfully restored. Our study highlights a pathological role of cochlear GLSs by identifying a novel deafness gene and its causal relationship with ANSD.

Download Full-text

The Role of Temporal Envelope and Fine Structure in Mandarin Lexical Tone Perception in Auditory Neuropathy Spectrum Disorder

PLoS ONE ◽

10.1371/journal.pone.0129710 ◽

2015 ◽

Vol 10 (6) ◽

pp. e0129710 ◽

Cited By ~ 7

Author(s):

Shuo Wang ◽

Ruijuan Dong ◽

Dongxin Liu ◽

Yuan Wang ◽

Bo Liu ◽

...

Keyword(s):

Fine Structure ◽

Auditory Neuropathy ◽

Spectrum Disorder ◽

Lexical Tone ◽

Temporal Envelope ◽

Auditory Neuropathy Spectrum Disorder ◽

Tone Perception

Download Full-text

Effectiveness of Channel-Free Hearing Aid and Noise Desensitisation Training in Auditory Neuropathy Spectrum Disorder - Single Case Study

International Journal of Health Sciences and Research ◽

10.52403/ijhsr.20211020 ◽

2021 ◽

Vol 11 (10) ◽

pp. 162-168

Author(s):

Sreebha Sreedhar ◽

Nihala K P ◽

Aleesha M H

Keyword(s):

Hearing Aids ◽

Signal To Noise Ratio ◽

Single Case ◽

Auditory Brainstem ◽

Auditory Neuropathy ◽

Spectrum Disorder ◽

Single Case Study ◽

Speech Discrimination ◽

Auditory Neuropathy Spectrum Disorder

Auditory Neuropathy Spectrum Disorder is a rare condition wherein neural transmission through the VIIIth nerve and auditory brainstem is disrupted with intact peripheral hearing. Most frequently reported symptoms by individuals suffering from such conditions include impaired speech discrimination especially in presence of background noise. The aim of this single case study is to emphasize the effectiveness of channel-free technology as a rehabilitative option and to demonstrate the improvement in speech perception in noise with noise desensitisation training. A 24-year-old male patient reported to the National Institute of Speech and Hearing with the complaint of poor speech comprehension. The audiological profile revealed, bilateral moderate sensorineural hearing loss in pure tone audiometry with poor speech discrimination scores, bilateral ‘A’ type tympanogram with absent acoustic reflexes, good signal to noise ratio in otoacoustic emissions, and absent Auditory Brainstem Response at 95 dBnHL bilaterally suggestive of auditory neuropathy spectrum disorder in both the ears. As a part of rehabilitation, hearing aids with multiple channels and channel-free technology were tried and better speech discrimination scores were obtained with channel-free technology. In order to address poor speech discrimination in presence of noise, noise desensitisation training was given at different Signal to Noise Ratio with channel-free hearing aids and was found to be effective in improving the speech discrimination scores especially in adverse listening conditions. Key words: Auditory neuropathy spectrum disorder, Channel free hearing aid, Noise desensitisation.

Download Full-text