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

Abstract

BackgroundVacuolar-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 a3 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 FindingsX-ray microtomography showed narrowed foramina in the skull, suggesting that optic nerve compression occurred in the a3-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 a3 subunit accumulated in the choriocapillary meshwork in uveal tissues. Two other subunit isoforms a1 and a2 accumulated in the retinal photoreceptor layer. We found that the a4 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 a4 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.ConclusionsOur findings suggest that a similar etiology of visual impairment is involved in both humans and mice; thus, a3-deficient mice may provide a suitable model for clinical and diagnostic purposes in cases of ARO.

Atp6v0a4 knockout mouse is a model of distal renal tubular acidosis with hearing loss, with additional extrarenal phenotype

“…Loss of the early expression detected in developing ear is likely to have resulted in the gross anatomical and functional abnormalities found in Atp6v0a4 −/− animals. Expression of a4 in the developing eye is consistent with known localization in adult mouse pigmented epithelial cells of the retina and ciliary bodies (22). In contrast, although the presence of H + -ATPase has previously been reported in penile urethra in rat (23), a4 was not sought as a subunit at this site.…”

Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

“…In addition to V0a3 being a component of the lysosomal v-ATPase, osteoclasts express the V0a3 isoform of the V0a subunit and use the v-ATPase to acidify extracellular compartments for bone reabsorption (Toyomura et al, 2003). Retinal degeneration was observed in mice lacking V0a3 which could explain the visual impairments observed in ARO (Kawamura et al, 2010). Mutations in the V0a2 gene cause autosomal recessive cutis laxa type II (ARCLII) and Wrinkly Skin Syndrome (WSS ), two related developmental disorders characterized by decreased skin elasticity connective tissue weakness, osteoporosis, (Allanson et al, 1986; Kornak et al, 2008; Morava et al, 2008; Patton et al, 1987).…”

Production and Physiological Effects of Hydrogen Sulfide

“…An increase in intracellular calcium levels occurs during apoptotic cell death, and this may activate calcium-dependent proteases, such as calpain. Voltage-gated Ca 2 + channel blockers such as diltiazem suppress photoreceptor cell apoptosis, and the lack of the V-ATPase a3 subunit causes retinal degeneration, suggesting that voltage-gated Ca 2 + channels and V-ATPase are involved in photoreceptor degeneration (19,38). H 2 S activates V-ATPase in horizontal cells to release protons, which suppress voltage-gated Ca 2 + channels in photoreceptor cells, thereby maintaining intracellular Ca 2 + concentrations at low levels in photoreceptor cells (Fig.…”