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Int J Med Sci. 2017 Feb 23;14(3):246-256. doi: 10.7150/ijms.17785. eCollection 2017.

Functional analysis of a nonsyndromic hearing loss-associated mutation in the transmembrane II domain of the GJC3 gene.

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Department of BioMedical Sciences, Chung Shan Medical University, Taichung, Taiwan;; Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Department of Otolaryngology, Cathay General Hospital, Taipei, Taiwan.
Department of BioMedical Sciences, Chung Shan Medical University, Taichung, Taiwan.
Department of BioMedical Sciences, Chung Shan Medical University, Taichung, Taiwan;; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.


In a previous study, we identified a novel missense mutation, p.W77S, in the GJC3 gene encoding connexin30.2/connexin31.3 (CX30.2/CX31.3) from patients with hearing loss. The functional alteration of CX30.2/CX31.3 caused by the p.W77S mutant of GJC3 gene, however, remains unclear. In the current study, our result indicated that the p.W77 is localized at the second membrane-spanning segments (TM2) and near border of the E1 domain of the CX30.2/CX31.3 protein and highly conserved (Conseq score = 8~9) in all species. The p.W77S missense mutation proteins in the intracellular distribution are different CX30.2/CX31.3WT and an accumulation of the mutant protein in the endoplasmic reticulum (ER) of the HeLa cell. Furthermore, co-expression of WT and p.W77S mutant chimerae proteins showed that the heteromeric connexon accumulated in the cytoplasm, thereby impairing the WT proteins' expression in the cell membranes. In addition, we found that CX30.2/CX31.3W77S missense mutant proteins were degraded by lysosomes and proteosomes in the transfected HeLa cell. Based on these findings, we suggest that p.W77S mutant has a dominant negative effect on the formation and function of the gap junction. These results give a novel molecular elucidation for the mutation of GJC3 in the development of hearing loss.


CX30.2/CX31.3; GJC3; hearing loss.; mutation

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