title: Trafficking abnormality and ER stress underlie functional deficiency of hearing impairment-associated connexin-31 mutants.
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.
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha 410083, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Xia
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.forename: Hui
authors.initials: H
authors.lastname: Xiong
authors.forename: Qian
authors.initials: Q
authors.lastname: Pan
authors.forename: Liangqun
authors.initials: L
authors.lastname: Huang
authors.forename: Danling
authors.initials: D
authors.lastname: Wang
authors.forename: Zhuohua
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017630:Connexins / Q000235:genetics*; D007758:Ear, Inner / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000502:physiology*; D017629:Gap Junctions / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism; D034381:Hearing Loss / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics*; D013312:Stress, Physiological
chemical_list: D017630:Connexins; C558577:connexin 31, mouse