Loss of Gap Junction Delta-2 (GJD2) gene orthologs leads to refractive error in zebrafish

Myopia is the most common developmental disorder of juvenile eyes, and it has become an increasing cause of severe visual impairment. The GJD2 locus has been consistently associated with myopia in multiple independent genome-wide association studies. However, despite the strong genetic evidence, little is known about the functional role of GJD2 in refractive error development. Here, we find that depletion of gjd2a (Cx35.5) or gjd2b (Cx35.1) orthologs in zebrafish, cause changes in the biometry and refractive status of the eye. Our immunohistological and scRNA sequencing studies show that Cx35.5 (gjd2a) is a retinal connexin and its depletion leads to hyperopia and electrophysiological changes in the retina. These findings support a role for Cx35.5 (gjd2a) in the regulation of ocular biometry. Cx35.1 (gjd2b) has previously been identified in the retina, however, we found an additional lenticular role. Lack of Cx35.1 (gjd2b) led to a nuclear cataract that triggered axial elongation. Our results provide functional evidence of a link between gjd2 and refractive error. Quint et al. use zebrafish lines deficient in one of two orthologs of the Gap Junction Delta-2 (GJD2) gene, which is associated with myopia by genome-wide association studies. They link gjd2 with refractive error and report evidence to suggest that gjd2a plays a role in ocular biometry whilst gjd2b, previously found in the retina, possesses an additional lenticular role.

Automated summary

The study reveals the association of the GJD2 gene with myopia, with gjd2a playing a regulatory role in ocular biometry and gjd2b having an additional role in the crystalline lens besides being found in the retina.