Ocular pathology relevant to glaucoma in a Gja1 ^Jrt/+ mouse model of human oculodentodigital dysplasia

Purpose. Oculodentodigital dysplasia (ODDD) is a human disorder caused by mutations in the gap junction alpha 1 (GJA1) gene encoding the connexin43 (Cx43) gap junction protein. Causal links between GJA1 mutations and glaucoma are not understood. The purpose in this study was to examine the ocular phenotype for Gja1 ^Jrt/+ mice harboring a Cx43 G60S mutation. Methods. In young Gja1 ^Jrt/+ mice, Cx43 abundance was assessed with a Western blot, and Cx43 localization was visualized using immunohistochemistry and confocal microscopy. Intraocular pressure (IOP) was measured by rebound tonometry, and eye anatomy was imaged using ocular coherence tomography (OCT). Hematoxylin and eosin (H&E)-stained eye sections were examined for ocular histopathology related to the development of glaucoma. Results. Decreased Cx43 protein levels were evident in whole eyes from Gja1 ^Jrt/+ mice compared with those of wild-type mice at postnatal day 1 (P = 0.005). Cx43 immunofluorescence in ciliary bodies of Gja1 ^Jrt/+ mice was diffuse and intracellular, unlike the gap junction plaques prevalent in wildtype mice. IOP in Gja1 ^Jrt/+ mice changed during postnatal development, with significantly lower IOP at 21 weeks of age in comparison to the IOP of wild-type eyes. Microphthalmia, enophthalmia, anterior angle closure, and reduced pupil diameter were observed in Gja1 ^Jrt/+ mice at all ages examined. Ocular histology showed prominent separations between the pigmented and nonpigmented ciliary epithelium of Gja1 ^Jrt/+ mice, split irides, and alterations in the number and distribution of nuclei in the retina. Conclusions. Detailed phenotyping of Gja1 ^Jrt/+ eyes offers a framework for elucidating human ODDD ocular disease mechanisms and evaluating new treatments designed to protect ocular synaptic network integrity.