Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, United States; Institute for Vision Research, University of Iowa, Iowa City, IA, United States.
Institute for Vision Research, University of Iowa, Iowa City, IA, United States; Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, United States.
Vision Res. 2024 Oct;223:108464. doi: 10.1016/j.visres.2024.108464. Epub 2024 Aug 15.
Exfoliation syndrome is a leading cause of secondary glaucoma worldwide. Among the risk-factors for exfoliation syndrome and exfoliation glaucoma that have been investigated, a genetic association with 15q24.1 is among the most striking. The leading candidates for the causal gene at this locus are LOXL1 and/or LOXL1-AS1, but studies have not yet coalesced in establishing, or ruling out, either candidate. Here, we contribute to studies of the 15q24.1 locus by making a partially humanized mouse model in which 166 kb of human genomic DNA from the 15q24.1 locus was introduced into the mouse genome via BAC transgenesis (B6-Tg(RP11-71M11)Andm). Transgenic expression of human genes in the BAC was only detectable for LOXL1-AS1. One cohort of 34 mice (21 experimental hemizygotes and 13 non-carrier control littermates) was assessed by slit-lamp exams and SD-OCT imaging at early (1-2 months) and mid (4-5 months) time points; fundus exams were performed at 5 months of age. A second smaller cohort (3 hemizygotes) were aged extensively (>12 months) to screen for overt abnormalities. Across all genotypes and ages, 136 slit-lamp exams, 128 SD-OCT exams, and 42 fundus exams detected no overt indices of exfoliation syndrome. Quantitatively, small, but statistically significant, age-related declines in ganglion cell complex thickness and total retinal thickness were detected in the hemizygotes at 4 months of age. Overall, this study demonstrates complexity in gene regulation from the 15q24.1 locus and suggests that LOXL1-AS1 is unlikely to be a monogenic cause of exfoliation syndrome but may contribute to glaucomatous retinal damage.
剥脱综合征是全球继发性青光眼的主要病因。在已研究过的与剥脱综合征和剥脱性青光眼相关的风险因素中，与 15q24.1 的遗传关联最为显著。该基因座的主要候选致病基因是 LOXL1 和/或 LOXL1-AS1，但研究尚未确定或排除这两个候选基因。在这里，我们通过制作部分人源化小鼠模型来研究 15q24.1 基因座，该模型通过 BAC 转基因技术（B6-Tg(RP11-71M11)Andm）将来自 15q24.1 基因座的 166 kb 人基因组 DNA 引入小鼠基因组。仅可检测到人 BAC 中 LOXL1-AS1 的基因表达。一组 34 只小鼠（21 只实验性半合子和 13 只非携带者对照同窝仔）通过裂隙灯检查和 SD-OCT 成像在早期（1-2 个月）和中期（4-5 个月）进行评估；在 5 个月大时进行眼底检查。第二个较小的队列（3 只半合子）被广泛（>12 个月）老化以筛查明显异常。在所有基因型和年龄中，136 次裂隙灯检查、128 次 SD-OCT 检查和 42 次眼底检查均未发现剥脱综合征的明显指标。定量分析显示，在 4 个月大的半合子中，视神经节细胞复合体厚度和总视网膜厚度随年龄增长出现了小但有统计学意义的下降。总的来说，这项研究表明 15q24.1 基因座的基因调控非常复杂，并且表明 LOXL1-AS1 不太可能是剥脱综合征的单基因病因，但可能导致青光眼性视网膜损伤。
