Trantow Colleen M, Mao Mao, Petersen Greg E, Alward Erin M, Alward Wallace L M, Fingert John H, Anderson Michael G
Department of Molecular Physiology, University of Iowa, Iowa City, Iowa 52242, USA.
Invest Ophthalmol Vis Sci. 2009 Mar;50(3):1205-14. doi: 10.1167/iovs.08-2791. Epub 2008 Nov 21.
Human eyes with exfoliation syndrome (XFS) exhibit a distinctive pattern of iris transillumination defects that are recapitulated in Lyst mutant mice carrying the beige allele. The purpose of this study was to determine the anatomic basis for Lyst-mediated transillumination defects, test whether Lyst mutant mice develop other features of XFS, and describe the molecular basis of the beige mutation.
Lyst mutant mice and strain-matched controls were compared by clinical, histologic, immunohistochemical, and molecular genetic analyses.
Slit-lamp examination showed that Lyst mutant mice uniformly exhibit XFS-like transillumination defects. Histologic analysis showed that these defects correlate with a sawtooth morphology of the iris pigment epithelium. Lyst mutant mice also produce an exfoliative-like material and exhibit pronounced pigment dispersion. Despite these insults, Lyst mutation does not cause increased intraocular pressure or optic nerve damage in the C57BL/6J genetic background. Sequence analysis identified that the beige mutation is predicted to delete a single isoleucine from the WD40 domain of the LYST protein, suggesting that this mutation is likely to disrupt a protein-protein interaction.
Lyst mutant eyes exhibit multiple features of XFS. Recent human genetic association studies have identified changes occurring in the LOXL1 gene as an important risk factor for XFS but also indicated that other factors contributing to risk likely exist. These results demonstrated that mutation of the Lyst gene can produce ocular features of human XFS and suggested that LYST or LYST-interacting genes may contribute to XFS.
患有剥脱综合征（XFS）的人眼表现出独特的虹膜透照缺损模式，这种模式在携带米色等位基因的Lyst突变小鼠中也有重现。本研究的目的是确定Lyst介导的透照缺损的解剖学基础，测试Lyst突变小鼠是否会出现XFS的其他特征，并描述米色突变的分子基础。
通过临床、组织学、免疫组织化学和分子遗传学分析比较Lyst突变小鼠和品系匹配的对照小鼠。
裂隙灯检查显示，Lyst突变小鼠均表现出类似XFS的透照缺损。组织学分析表明这些缺损与虹膜色素上皮的锯齿状形态相关。Lyst突变小鼠还产生类似剥脱的物质并表现出明显的色素播散。尽管有这些损害，但在C57BL/6J遗传背景下，Lyst突变不会导致眼压升高或视神经损伤。序列分析确定米色突变预计会从LYST蛋白的WD40结构域中删除一个异亮氨酸，这表明该突变可能会破坏蛋白质-蛋白质相互作用。
Lyst突变眼表现出XFS的多种特征。最近的人类基因关联研究已确定LOXL1基因发生的变化是XFS的一个重要风险因素，但也表明可能存在其他导致风险的因素。这些结果表明Lyst基因的突变可产生人类XFS的眼部特征，并提示LYST或与LYST相互作用的基因可能与XFS有关。
