[14] As a member of the connexin family, GJA1 is a component of gap junctions, which are intercellular channels that connect adjacent cells to permit the exchange of low molecular weight molecules, such as small ions and secondary messengers, to maintain homeostasis.

[7][8] For instance, transforming growth factor-beta 1 (TGF-β1) was observed to induce GJA1 expression via the Smad and ERK1/2 signaling pathways, resulting in trophoblast cell differentiation into the placenta.

[13] GJA1 has also been observed to localize to the mitochondria, where it promotes cell survival by downregulating the intrinsic apoptotic pathway during conditions of oxidative stress.

[12] Ultimately, GJA1 has low tolerance for deviations from its original sequence, with mutations resulting in loss- or gain-of-channel function that lead to disease phenotypes.

[12] It is paradoxical, however, that patients with an array of somatic mutations in GJA1 most often do not present with cardiac arrhythmias, even though connexin-43 is the most abundant protein forming gap junctional pores in cardiomyocytes and are essential for normal action potential propagation.

[9][15] Moreover, the cytoprotective effects of this protein can promote tumor cell survival in radiotherapy treatments, while silencing its gene increases radiosensitivity.

[19] Currently, only rotigaptide, an antiarrhythmic peptide-based drug, and its derivatives, such as danegaptide, have reached clinical trials for treating cardiac pathologies by enhancing GJA1 expression.

[12] Thus, a more effective approach entails designing a miRNA through antisense oligonucleotides, transfection, or infection to knock down only mutant GJA1 mRNA, thus allowing the expression of wildtype GJA1 and retaining normal phenotype.