Department of Biochemistry, Faculty of Pharmaceutical Sciences, Doshisha Women's College, Kyotanabe, Japan.
PLoS One. 2010 Aug 10;5(8):e12086. doi: 10.1371/journal.pone.0012086.
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 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 FINDINGS: X-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.
Our 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.
液泡型质子转运 ATP 酶（V-ATPase）参与视觉功能的正常发育。编码 V-ATPase 的 a3 亚基的 Tcirg1（也称为 Atp6V0a3）基因的突变导致人类严重的常染色体隐性骨硬化症（ARO）。ARO 通常与视力受损有关，很可能是因为视神经在视神经管中受压。我们检查了 Tcirg1 功能缺失的小鼠的眼部表型。
方法/主要发现：X 射线断层摄影显示颅骨中的孔变窄，这表明在 a3 缺陷（Tcirg1-/-）小鼠中发生了视神经压迫。突变小鼠的视网膜具有正常的结构，但在出生后 2-3 周时凋亡细胞的数量增加。在眼部系统中，a3 亚基在葡萄膜组织的脉络膜毛细血管网中积累。另外两种亚基同工型 a1 和 a2 在视网膜光感受器层中积累。我们发现，以前曾显示其表达仅限于几种转运上皮的 a4 亚基在视网膜色素上皮细胞和睫状体中丰富。在野生型小鼠中，a4 在葡萄膜组织中的表达低于检测水平，但在突变的脉络膜毛细血管网中增加，这表明在突变组织中 a 亚基同工型可能发生了代偿。
我们的研究结果表明，人类和小鼠的视力障碍具有相似的病因；因此，a3 缺陷型小鼠可能为 ARO 的临床和诊断目的提供合适的模型。
