Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Jang MW

PROVIDER: S-EPMC8179140 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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

Jang Minwoo Wendy MW Oh Doo-Yi DY Yi Eunyoung E Liu Xuezhong X Ling Jie J Kim Nayoung N Sharma Kushal K Kim Tai Young TY Lee Seungmin S Kim Ah-Reum AR Kim Min Young MY Kim Min-A MA Lee Mingyu M Han Jin-Hee JH Han Jae Joon JJ Park Hye-Rim HR Kim Bong Jik BJ Lee Sang-Yeon SY Woo Dong Ho DH Oh Jayoung J Oh Soo-Jin SJ Du Tingting T Koo Ja-Won JW Oh Seung-Ha SH Shin Hyun-Woo HW Seong Moon-Woo MW Lee Kyu-Yup KY Kim Un-Kyung UK Shin Jung Bum JB Sang Shushan S Cai Xinzhang X Mei Lingyun L He Chufeng C Blanton Susan H SH Chen Zheng-Yi ZY Chen Hongsheng H Liu Xianlin X Nourbakhsh Aida A Huang Zaohua Z Kang Kwon-Woo KW Park Woong-Yang WY Feng Yong Y Lee C Justin CJ Choi Byung Yoon BY

Proceedings of the National Academy of Sciences of the United States of America 20210601 22

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 ...[more]

PMID: 34050020

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Project description:To define the phenotype and elucidate the molecular basis for an autosomal recessively inherited optic atrophy and auditory neuropathy in a consanguineous family with two affected children.Family members underwent detailed ophthalmologic, electrophysiological, and audiological assessments. An autozygosity mapping strategy using high-density single nucleotide polymorphism microarrays and microsatellite markers was used to detect regions of genome homozygosity that might contain the disease gene. Candidate genes were then screened for mutations by direct sequencing.Both affected subjects had poor vision from birth and complained of progressive visual loss over time. Current visual acuity ranged from 6/60 to 6/120. Fundus examination revealed bilateral temporal optic nerve pallor in both patients with otherwise normal retinal findings. International-standard full-field electroretinograms were normal in both individuals, with no evidence of generalized retinal dysfunction. Pattern cortical visual evoked potentials were grossly abnormal bilaterally in both cases. The pattern electroretinogram N95:P50 ratio was subnormal, and the P50 was of shortened peak time bilaterally in both patients. The electrophysiological findings were consistent with bilateral retinal ganglion cell/optic nerve dysfunction. Audiological investigation in both siblings revealed abnormalities falling within the auditory neuropathy/dysynchrony spectrum. There were no auditory symptoms and good outer hair cell function (as demonstrated by transient evoked otoacoustic emissions) but impaired inner hair cell/neural function with abnormal stapedial reflex thresholds and abnormal or absent auditory brainstem-evoked responses. The single nucleotide polymorphism microarray data demonstrated a 24.17 Mb region of homozygosity at 11q14.1-11q22.3, which was confirmed by microsatellite marker analysis. The candidate target region contained the transmembrane protein 126A (TMEM126A) gene, and direct sequencing identified a previously described nonsense mutation (c.163C>T; p.Arg55X).We describe the first detailed phenotyping of patients with autosomal recessive TMEM126A-associated optic atrophy and auditory neuropathy. These findings will facilitate the identification of individuals with this recently described disorder.

Dataset Information

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

Publications

A nonsense <i>TMEM43</i> variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder.

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