C57BL/6NCya-Gjc3^em1/Cya

Gjc3, also known as connexin 30.2/31.3 or Cx31.3, is a member of the connexin family proteins. Connexins assemble into hexameric channels called hemichannels/connexons, which can function as transmembrane channels or form gap junction intercellular channels (GJIChs) [2]. Gjc3 is expressed in oligodendroglia and is involved in cell-cell communication processes that are crucial for normal physiological functions [5].

Functional studies on Gjc3 have mainly focused on its role in non-syndromic hearing loss. Missense mutations in Gjc3, such as p.W77S, p.R15G, and p.L23H, have been identified in patients with hearing loss. These mutant proteins show abnormal intracellular distribution, for example, the p.W77S mutant accumulates in the endoplasmic reticulum of HeLa cells. Co-expression of wild-type and mutant proteins leads to cytoplasmic accumulation of heteromeric connexons, impairing wild-type protein expression in cell membranes. Additionally, mutant proteins are degraded by lysosomes and proteosomes. Moreover, cells carrying mutant Gjc3 genes have reduced ATP release (hemichannel function) compared to wild-type expressing cells, suggesting that mutations in Gjc3 result in a loss of hemichannel function of the CX30.2/CX31.3 protein, possibly causing hearing loss [3,4]. However, a study in Ghana demonstrated that Gjc3 genes may not contribute significantly to hearing impairment in this population, though a larger population study was proposed to confirm this [1].

In conclusion, Gjc3 is important for cell-cell communication, potentially through its role in forming hemichannels and gap junctions. Functional studies, especially those examining missense mutations in Gjc3, suggest its significance in non-syndromic hearing loss. However, the extent of its contribution to hearing impairment may vary among different populations. Understanding Gjc3's function can provide insights into the molecular mechanisms underlying non-syndromic hearing loss [1,3,4].

References:

1. Adadey, Samuel M, Esoh, Kevin K, Quaye, Osbourne, Awandare, Gordon A, Wonkam, Ambroise. 2020. GJB4 and GJC3 variants in non-syndromic hearing impairment in Ghana. In Experimental biology and medicine (Maywood, N.J.), 245, 1355-1367. doi:10.1177/1535370220931035. https://pubmed.ncbi.nlm.nih.gov/32524838/

2. Lee, Hyuk-Joon, Jeong, Hyeongseop, Hyun, Jaekyung, Yoo, Jejoong, Woo, Jae-Sung. 2020. Cryo-EM structure of human Cx31.3/GJC3 connexin hemichannel. In Science advances, 6, eaba4996. doi:10.1126/sciadv.aba4996. https://pubmed.ncbi.nlm.nih.gov/32923625/

3. Wong, Swee-Hee, Wang, Wen-Hung, Chen, Pin-Hua, Li, Shuan-Yow, Yang, Jiann-Jou. 2017. Functional analysis of a nonsyndromic hearing loss-associated mutation in the transmembrane II domain of the GJC3 gene. In International journal of medical sciences, 14, 246-256. doi:10.7150/ijms.17785. https://pubmed.ncbi.nlm.nih.gov/28367085/

4. Su, Ching-Chyuan, Li, Shuan-Yow, Yen, Yung-Chang, Liang, Wei-Guang, Yang, Jiann-Jou. . Mechanism of two novel human GJC3 missense mutations in causing non-syndromic hearing loss. In Cell biochemistry and biophysics, 66, 277-86. doi:10.1007/s12013-012-9481-8. https://pubmed.ncbi.nlm.nih.gov/23179405/

5. Abrams, Charles K. 2023. Mechanisms of Diseases Associated with Mutation in GJC2/Connexin 47. In Biomolecules, 13, . doi:10.3390/biom13040712. https://pubmed.ncbi.nlm.nih.gov/37189458/