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Anson K. Li, Justin G. Mayers, Kathleen A. Hill; Human ODDD-retinal Degeneration Mimicked By A Mouse Mutant Reveals Early Diagnostic Markers And Disease Mechanisms. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2481.
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Oculodentodigital dysplasia (ODDD) is characterized by ocular abnormalities including microphthalmia, enophthalmia, iris malformation and microcornea. A recent clinical report (Gabriel et al, 2011. Arch Ophthalmol 129: 781) examined two ODDD patients and found optic nerve and retinal aberrations not emphasized previously. Also, ciliary body cysts in one patient had not been associated with human ODDD previously. Gja1Jrt/+ mice, a mimic of human ODDD, have ciliary body cysts and retinal abnormalities (Tsui et al. IOVS 52:3539). Gja1Jrt/+ mice carry a glycine to serine substitution at position 60 (G60S) in connexin43, the product of the gap junction alpha 1 (Gja1) gene. Connexins form gap junctions between cells in multiple structures of the eye: ciliary body, lens, iris and retina. The purpose of this project was to show the high prevalence of retinal aberrations in older ODDD mice and the correlation between anterior segment phenotype and the mutant domain of the protein.
Intraocular pressure of n=9 Gja1Jrt/+ and n=9 wild-type 31 to 48-week-old male mice was measured by rebound tonometry. Whole eye and retinal structure were imaged using Visante™ Ocular Coherence Tomography (OCT). Hematoxylin and eosin-stained eye cross sections were examined for the structural abnormalities typical of the anterior segment of the ODDD phenotype. Retinal layer thickness and nuclear counts were compared between Gja1Jrt/+ and wild-type mice.
Gja1Jrt/+ mice showed the G60S ODDD anterior segment phenotype with split iris and vesicle-filled ciliary body with normal intraocular pressure. All Gja1Jrt/+ mice showed undulations of the outer nuclear layer with cell loss (p<0.05) and thinning of the outer plexiform layer (p<0.05) of the retina. Two Gja1Jrt/+ mice with severe disease also had lens degradation.
A human ODDD patient and Gja1Jrt/+ mice, both with a mutation in the first Connexin43 extracellular domain, have similar ocular phenotypes that progress to retinal degeneration. Increased IOP and ganglion cell loss in humans associated with glaucoma, was not observed in Gja1Jrt/+ mice, suggesting these features may be insufficient in diagnosing glaucoma. Anterior segment and retinal imaging better track disease onset and progression.
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