From the Vanderbilt Eye Institute, Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center (R.W.K., S.I., J.K.), Nashville, Tennessee; Department of Molecular Physiology and Biophysics, Vanderbilt University (R.W.K.), Nashville, Tennessee.
From the Vanderbilt Eye Institute, Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center (R.W.K., S.I., J.K.), Nashville, Tennessee.
Am J Ophthalmol. 2024 Nov;267:271-285. doi: 10.1016/j.ajo.2024.06.015. Epub 2024 Jun 22.
Exfoliation syndrome (XFS) is a systemic connective tissue disorder with elusive pathophysiology. We hypothesize that a mouse model with elastic fiber defects caused by lack of lysyl oxidase like 1 (LOXL1 encoded by Loxl1), combined with microfibril deficiency due to Fbn1 mutation (encoding fibrillin-1, Fbn1) will display ocular and systemic phenotypes of XFS.
Loxl1 was crossed with Fbn1 to create double mutant (dbm) mice. Intraocular pressure (IOP), visual acuity (VA), electroretinogram (ERG), and biometry were characterized in 4 genotypes (wt, Fbn1, Loxl1, dbm) at 16 weeks of age. Optic nerve (ON) area was measured by ImageJ, and axon counting was achieved by AxonJ. Deep whole-body phenotyping was performed in wt and dbm mice. Two-tailed Student t test was used for statistical analysis.
There was no difference in IOP between the 4 genotypes. VA was significantly reduced only in dbm mice. The majority of biometric parameters showed significant differences in all 3 mutant genotypes compared with wt, and dbm had exacerbated anomalies compared with single mutants. Dbm mice showed reduced retinal function and significantly enlarged ON area compared with wt. Dbm mice exhibited severe systemic phenotypes related to abnormal elastic fibers, such as pelvic organ prolapse and cardiovascular and pulmonary abnormalities.
Ocular and systemic findings in dbm mice support functional overlap between fibrillin-1 and LOXL1, 2 prominent components of exfoliation material. Although no elevated IOP or reduction of axon numbers was detected in dbm mice at 16 weeks of age, their reduced retinal function and enlarged ON area indicate early retinal ganglion cell dysfunction. Dbm mice also provide insight on the link between XFS and systemic diseases in humans. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.
剥脱综合征（XFS）是一种具有难以捉摸的病理生理学的系统性结缔组织疾病。我们假设，由于缺乏赖氨酰氧化酶样 1（由 Loxl1 编码）导致弹性纤维缺陷，以及由于 Fbn1 突变（编码原纤维蛋白-1，Fbn1）导致微纤维缺乏的小鼠模型，将表现出 XFS 的眼部和全身表型。
将 Loxl1 与 Fbn1 进行杂交，以创建双突变（dbm）小鼠。在 16 周龄时，对 4 种基因型（wt、Fbn1、Loxl1、dbm）的眼内压（IOP）、视力（VA）、视网膜电图（ERG）和生物测量进行了特征描述。通过 ImageJ 测量视神经（ON）面积，并通过 AxonJ 进行轴突计数。在 wt 和 dbm 小鼠中进行了深度全身表型分析。使用双尾学生 t 检验进行统计分析。
4 种基因型之间的 IOP 没有差异。只有 dbm 小鼠的 VA 显著降低。与 wt 相比，大多数生物测量参数在所有 3 种突变基因型中均存在显著差异，dbm 与单突变体相比具有更严重的异常。dbm 小鼠的视网膜功能降低，与 wt 相比，ON 面积显著增大。dbm 小鼠表现出与异常弹性纤维相关的严重全身性表型，如盆腔器官脱垂和心血管及肺部异常。
dbm 小鼠的眼部和全身发现支持原纤维蛋白-1 和 LOXL1（剥脱物的 2 个主要成分）之间的功能重叠。尽管在 16 周龄时，dbm 小鼠未检测到升高的 IOP 或轴突数量减少，但它们的视网膜功能降低和 ON 面积增大表明早期视网膜神经节细胞功能障碍。dbm 小鼠还为 XFS 与人类系统性疾病之间的联系提供了深入了解。
本文的发表得到了美国眼科学会的赞助。
