GJB6, also known as connexin 30, is a gene encoding a gap junction protein. Gap junction proteins are involved in transcellular signaling, metabolic supply, and fluid homeostasis in the human cochlea [1]. Mutations in GJB6 are associated with non-syndromic hearing impairment, making it an important gene for understanding hereditary hearing loss [2,3,4,5,6]. Mouse models, such as the Dfnb1em274 murine model generated using CRISPR-Cas9, are valuable for studying GJB6-related functions and pathologies [2].

In the Dfnb1em274 murine model, which recapitulates the del(GJB6-D13S1830) deletion seen in human DFNB1 hearing impairment, homozygous mice have profound hearing loss (>90 dB SPL) [2]. This is due to nearly abolished Gjb2 expression and near-absence of its protein product, Cx26, throughout the cochlea, indicating that the GJB6-related deletion affects Gjb2 expression and leads to cochlear structural abnormalities causing hearing loss [2].

In conclusion, GJB6 is crucial for normal cochlear function, especially in maintaining proper transcellular communication in the cochlea. The Dfnb1em274 KO mouse model has been instrumental in revealing the pathological mechanisms of DFNB1-associated hearing impairment, which is related to the regulation of Gjb2 expression by GJB6-related genetic elements [2].

References:

1. Liu, Wei, Rask-Andersen, Helge. 2022. GJB2 and GJB6 gene transcripts in the human cochlea: A study using RNAscope, confocal, and super-resolution structured illumination microscopy. In Frontiers in molecular neuroscience, 15, 973646. doi:10.3389/fnmol.2022.973646. https://pubmed.ncbi.nlm.nih.gov/36204137/

2. Domínguez-Ruiz, María, Murillo-Cuesta, Silvia, Contreras, Julio, Varela-Nieto, Isabel, Del Castillo, Ignacio. 2024. A murine model for the del(GJB6-D13S1830) deletion recapitulating the phenotype of human DFNB1 hearing impairment: generation and functional and histopathological study. In BMC genomics, 25, 359. doi:10.1186/s12864-024-10289-z. https://pubmed.ncbi.nlm.nih.gov/38605287/

3. Buonfiglio, Paula, Bruque, Carlos D, Luce, Leonela, Elgoyhen, Ana Belén, Dalamón, Viviana. 2020. GJB2 and GJB6 Genetic Variant Curation in an Argentinean Non-Syndromic Hearing-Impaired Cohort. In Genes, 11, . doi:10.3390/genes11101233. https://pubmed.ncbi.nlm.nih.gov/33096615/

4. Pandya, Arti, O'Brien, Alexander, Kovasala, Michael, Tekin, Mustafa, Arnos, Kathleen S. 2020. Analyses of del(GJB6-D13S1830) and del(GJB6-D13S1834) deletions in a large cohort with hearing loss: Caveats to interpretation of molecular test results in multiplex families. In Molecular genetics & genomic medicine, 8, e1171. doi:10.1002/mgg3.1171. https://pubmed.ncbi.nlm.nih.gov/32067424/

5. Adadey, Samuel M, Manyisa, Noluthando, Mnika, Khuthala, Awandare, Gordon A, Wonkam, Ambroise. 2019. GJB2 and GJB6 Mutations in Non-Syndromic Childhood Hearing Impairment in Ghana. In Frontiers in genetics, 10, 841. doi:10.3389/fgene.2019.00841. https://pubmed.ncbi.nlm.nih.gov/31620164/

6. Tingang Wonkam, Edmond, Chimusa, Emile, Noubiap, Jean Jacques, F Fokouo, Jean Valentin, Wonkam, Ambroise. 2019. GJB2 and GJB6 Mutations in Hereditary Recessive Non-Syndromic Hearing Impairment in Cameroon. In Genes, 10, . doi:10.3390/genes10110844. https://pubmed.ncbi.nlm.nih.gov/31731535/