Trafficking abnormality and ER stress underlie functional deficiency of hearing impairment-associated connexin-31 mutants.
10.1007/s13238-010-0118-7
- Author:
Kun XIA
1
;
Hong MA
;
Hui XIONG
;
Qian PAN
;
Liangqun HUANG
;
Danling WANG
;
Zhuohua ZHANG
Author Information
1. State Key Laboratory of Medical Genetics, Central South University, Changsha 410083, China.
- Publication Type:Journal Article
- MeSH:
Animals;
Connexins;
genetics;
Ear, Inner;
metabolism;
Endoplasmic Reticulum;
physiology;
Gap Junctions;
genetics;
metabolism;
physiology;
Golgi Apparatus;
genetics;
metabolism;
Hearing Loss;
genetics;
metabolism;
pathology;
Mice;
Mutation;
Neurons;
metabolism;
Protein Transport;
genetics;
Stress, Physiological
- From:
Protein & Cell
2010;1(10):935-943
- CountryChina
- Language:English
-
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 HI-associated 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.
