Optic Nerve Compression and Retinal Degeneration in Tcirg1 Mutant Mice Lacking the Vacuolar-Type H+-ATPase a3 Subunit

Background Vacuolar-type proton transporting ATPase (V-ATPase) is involved in the proper development of visual function. Mutations in the Tcirg1 (also known as Atp6V0a3 ) locus, which encodes the a 3 subunit of V-ATPase, cause severe autosomal recessive osteopetrosis (ARO) in humans. ARO is often associated with impaired vision most likely because of nerve compression at the optic canal. We examined the ocular phenotype of mice deficient in Tcirg1 function. Methodology/Principal Findings X-ray microtomography showed narrowed foramina in the skull, suggesting that optic nerve compression occurred in the a 3-deficient ( Tcirg1 −/− ) mice. The retina of the mutant mice had normal architecture, but the number of apoptotic cells was increased at 2–3 wks after birth. In the ocular system, the a 3 subunit accumulated in the choriocapillary meshwork in uveal tissues. Two other subunit isoforms a 1 and a 2 accumulated in the retinal photoreceptor layer. We found that the a 4 subunit, whose expression has previously been shown to be restricted to several transporting epithelia, was enriched in pigmented epithelial cells of the retina and ciliary bodies. The expression of a 4 in the uveal tissue was below the level of detection in wild-type mice, but it was increased in the mutant choriocapillary meshwork, suggesting that compensation may have occurred among the a subunit isoforms in the mutant tissues. Conclusions Our findings suggest that a similar etiology of visual impairment is involved in both humans and mice; thus, a 3-deficient mice may provide a suitable model for clinical and diagnostic purposes in cases of ARO.