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. 2010 Nov 9;1(10):935–943. doi: 10.1007/s13238-010-0118-7

Trafficking abnormality and ER stress underlie functional deficiency of hearing impairmentassociated connexin-31 mutants

Kun Xia 1, Hong Ma 2, Hui Xiong 2, Qian Pan 1, Liangqun Huang 1, Danling Wang 1, Zhuohua Zhang 1,2,✉
PMCID: PMC4875122  PMID: 21204020

Abstract

Hearing impairment (HI) affects 1/1000 children and over 2% of the aged population. We have previously reported that mutations in the gene encoding gap junction protein connexin-31 (C×31) are associated with HI. The pathological mechanism of the disease mutations remains unknown. Here, we show that expression of C×31 in the mouse inner ear is developmentally regulated with a high level in adult inner hair cells and spiral ganglion neurons that are critical for the hearing process. In transfected cells, wild type C×31 protein (C×31wt) forms functional gap junction at cell-cell-contacts. In contrast, two HIassociated C×31 mutants, C×31R180X and C×31E183K resided primarily in the ER and Golgi-like intracellular punctate structures, respectively, and failed to mediate lucifer yellow transfer. Expression of C×31 mutants but not C×31wt leads to upregulation of and increased association with the ER chaperone BiP indicating ER stress induction. Together, the HI-associated C×31 mutants are impaired in trafficking, promote ER stress, and hence lose the ability to assemble functional gap junctions. The study reveals a potential pathological mechanism of HI-associated C×31 mutations.

Keywords: gap junction, bip, inner ear, protein folding

Footnotes

These authors contributed equally to the work.

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