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.

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The reactions of new chiral organic ligands trimesoyltri(L-alanine) (L-TMTAH(3)) or trimesoyltri(D-alanine) (D-TMTAH(3)) with transition metal salts in the presence of an ancillary ligand of 4,4'-bipyridine gave two pairs of three dimensional frameworks [Co(3)(L-TMTA)(2)(4,4'-bpy)(4)]·28H(2)O (1), [Co(3)(D-TMTA)(2)(4,4'-bpy)(4)]·28H(2)O (2) [Ni(3)(L-TMTA)(2)(4,4'-bpy)(4)]·2C(2)H(5)OH·14H(2)O (3) and [Ni(3)(D-TMTA)(2)(4,4'-bpy)(4)]·2C(2)H(5)OH·14H(2)O (4). These compounds were characterized by elemental analysis, IR, and X-ray powder diffraction analysis and the structures of 1-3 were determined from X-ray single crystal diffraction analysis. Complexes 1-4 feature linear trinuclear secondary building blocks [M(3)(COO)(4)](2+) formed via the connection of three metal ions by four carboxylato groups from four TMTA(3-) ligands. Every adjacent two linear trinuclear secondary building blocks are linked by one and three 4,4'-bipyridine molecules along the a and c axis, respectively, to form two-dimensional sheets, which are further connected by TMTA(3-) ligands to construct a porous three dimensional framework with one-dimensional channels. Compound 3 was taken as an example to investigate the adsorption properties of compounds 1-4. It revealed a saturated hydrogen uptake of 216.6 cm(3) g(-1) (2.0 wt%) at 11.1 atm measured at 77 K, a maximum CO(2) uptake of 119.4 cm(3) g(-1) (23.5 wt%) at 19.5 atm measured at 298 K and a saturated CH(4) uptake of 77.8 cm(3) g(-1) (5.6 wt%) at 27.1 atm measured at 298 K. The magnetic studies of complexes 1 and 3 indicate the presence of antiferromagnetic interactions between the metal ions in the two compounds.

Autosomal recessive non-syndromic hearing loss (ARNSHL) is a highly heterogeneous disease involving more than 70 pathogenic genes. However, most ARNSHL families have small-sized pedigrees with limited genetic information, rendering challenges for the molecular diagnosis of these patients. Therefore, we attempted to establish a strategy for identifying deleterious variants associated with ARNSHL by applying proband whole-exome sequencing (proband-WES). Aside from desiring to improve molecular diagnostic rates, we also aimed to search for novel deafness genes shared by patients with similar phenotype, making up for the deficiency of small ARNSHL families. In this study, 48.5% (16/33) families were detected the pathogenic variants in eight known deafness genes, including 10 novel variants identified in TMPRSS3 (MIM 605551), MYO15A (MIM 602666), TMC1 (MIM 606706), ADGRV1 (MIM 602851), and PTPRQ (MIM 603317). Apart from six novel variants with a truncating effect (nonsense, deletion, insertion, and splice-site), four novel missense variants were not found in 200 unrelated control population by using Sanger sequencing. It is important to note that none of novel genes were shared across different pedigrees, indicating that a larger sample size might be needed. Proband-WES is a cost-effective and precise way of identifying causative variants in nuclear families with ARNSHL. This economical strategy may be appropriated as a clinical application to provide molecular diagnostics, genetic counseling, and individualized health maintenance measures for patients with ARNSHL at hearing clinics.