Mechanism of two novel human GJC3 missense mutations in causing non-syndromic hearing loss
Abstract
Connexins (CXs), as a component of gap junction channel, are homologous four transmembrane-domain proteins, with numerous studies confirming their auditory functions. Among a cohort of patients having incurred non-syndromic hearing loss, we identified two novel missense mutations, p.R15G and p.L23H, in the GJC3 gene encoding CX30.2/CX31.3, as causally related to hearing loss in previous study. However, the functional alteration of CX30.2/CX31.3 caused by the mutant GJC3 gene remains unknown. In this study, we compared the intracellular distribution of mutant CX30.2/CX31.3 (p.R15G and p.L23H) with the wild-type (WT) protein in HeLa cells and the effect of the mutant protein had on those cells. Analytical results indicated that p.R15G and p.L23H mutant exhibited continuous staining along apposed cell membranes in the fluorescent localization assay, which is the same with the WT. Moreover, ATP release (hemichannel function) is less in HeLa cells carrying mutant GJC3 genes than those of WT expressing cells. We believe that although p.R15G and p.L23H mutants do not decrease the trafficking of CX proteins, mutations in GJC3 genes result in a loss of hemichannel function of CX30.2/CX31.3 protein, possibly causing hearing loss. Results of this study provide a novel molecular explanation for the role of GJC3 in hearing loss.
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Six positively selected genes were identified that conceivably evolved to increase auditory acuity over a wider range of frequencies in the carnivore ancestor and within Felidae.
“We identified six positively selected genes (Fig. 1) that conceivably evolved to increase auditory acuity over a wider range of frequencies in the carnivore ancestor and within Felidae, as mutations within each gene have been associated with autosomal, nonsyndromic deafness or hearing loss (22,23).”
From Comparative analysis of the domestic cat genome reveals genetic signatures underlying feline biology and domestication (2014) · cites this paper as [23]
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- Authors
- Su, C.-C., Li, S.-Y., Yen, Y.-C., Nian, J.-H., Liang, W.-G., & Yang, J.-J.
- Affiliations
- Chung Shan Medical University Hospital (TW)
- Min-Hwei College of Health Care Management (TW)
- Chung Shan Medical University (TW)
- Corresponding author
- Yang, Jiann-Jou
- Venue
- Cell Biochemistry and Biophysics
- Published
- 2012-11-22
- Volume
- 66
- Issue
- 2
- Pages
- 277-286
- ISSN
- 1085-9195 (ISSN-L)
- 1559-0283
- OpenAlex
- W2041164244
- Cited by
- 13
- References
- 59
- Citations by year
- 2026: 1 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 2 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 1 · 2014: 1
- FWCI
- 0.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Biochemistry and Biophysics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Chung Shan Medical University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
- Life Sciences › Neuroscience › Sensory Systems › Hearing, Cochlea, Tinnitus, Genetics
- Health Sciences › Medicine › Genetics › Congenital Ear and Nasal Anomalies
- Keywords
- non-syndromic hearing loss, missense mutations, ATP release, gap junction channels, protein trafficking, HeLa cells
- MeSH terms
- Amino Acid Sequence, Cloning, Molecular, HeLa Cells, Humans, Molecular Sequence Data, Nerve Tissue Proteins, Databases, Factual, Sequence Alignment, Protein Structure, Tertiary, Connexins, Computational Biology, Mutation, Missense, Hearing Loss
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