Department of Pathology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
PLoS One. 2010 Feb 4;5(2):e9050. doi: 10.1371/journal.pone.0009050.
Glaucoma is a leading cause of blindness worldwide. Nonetheless, the mechanism of its pathogenesis has not been well-elucidated, particularly at the molecular level, because of insufficient availability of experimental genetic animal models.
METHODOLOGY/PRINCIPAL FINDINGS: Here we demonstrate that deficiency of Vav2 and Vav3, guanine nucleotides exchange factors for Rho guanosine triphosphatases, leads to an ocular phenotype similar to human glaucoma. Vav2/Vav3-deficient mice, and to a lesser degree Vav2-deficient mice, show early onset of iridocorneal angle changes and elevated intraocular pressure, with subsequent selective loss of retinal ganglion cells and optic nerve head cupping, which are the hallmarks of glaucoma. The expression of Vav2 and Vav3 tissues was demonstrated in the iridocorneal angle and retina in both mouse and human eyes. In addition, a genome-wide association study screening glaucoma susceptibility loci using single nucleotide polymorphisms analysis identified VAV2 and VAV3 as candidates for associated genes in Japanese open-angle glaucoma patients.
CONCLUSIONS/SIGNIFICANCE: Vav2/Vav3-deficient mice should serve not only as a useful murine model of spontaneous glaucoma, but may also provide a valuable tool in understanding of the pathogenesis of glaucoma in humans, particularly the determinants of altered aqueous outflow and subsequent elevated intraocular pressure.
青光眼是全球致盲的主要原因之一。然而，由于缺乏实验性遗传动物模型，其发病机制，尤其是分子水平上的机制仍未得到充分阐明。
方法/主要发现：在这里，我们证明了 Rho 鸟苷三磷酸酶的鸟嘌呤核苷酸交换因子 Vav2 和 Vav3 的缺乏会导致类似于人类青光眼的眼部表型。Vav2/Vav3 缺陷型小鼠，以及程度较轻的 Vav2 缺陷型小鼠，表现出虹膜角膜角变化和眼内压升高的早期发作，随后选择性地丧失视网膜神经节细胞和视神经头凹陷，这是青光眼的标志。在人和小鼠的眼睛中，Vav2 和 Vav3 组织在虹膜角膜角和视网膜中都有表达。此外，使用单核苷酸多态性分析对青光眼易感基因座进行全基因组关联研究筛选，鉴定出 VAV2 和 VAV3 是日本开角型青光眼患者相关基因的候选基因。
结论/意义：Vav2/Vav3 缺陷型小鼠不仅可以作为自发性青光眼的有用小鼠模型，还可以为理解人类青光眼的发病机制，特别是改变房水流出和随后眼内压升高的决定因素提供有价值的工具。
