Journal article
Minimal phenotypes in transgenic mice with the human LOXL1/LOXL1-AS1 locus associated with exfoliation glaucoma
Vision research (Oxford), Vol.223, 108464
10/2024
DOI: 10.1016/j.visres.2024.108464
PMCID: PMC11381136
PMID: 39151208
Abstract
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.
Details
- Title: Subtitle
- Minimal phenotypes in transgenic mice with the human LOXL1/LOXL1-AS1 locus associated with exfoliation glaucoma
- Creators
- Kacie J. Meyer - University of IowaHannah E. Mercer - University of IowaBen R. Roos - University of IowaJohn H. Fingert - University of IowaMichael G. Anderson - Iowa City VA Health Care System
- Resource Type
- Journal article
- Publication Details
- Vision research (Oxford), Vol.223, 108464
- DOI
- 10.1016/j.visres.2024.108464
- PMID
- 39151208
- PMCID
- PMC11381136
- NLM abbreviation
- Vision Res
- ISSN
- 0042-6989
- eISSN
- 1878-5646
- Publisher
- Elsevier Ltd
- Grant note
- National Institutes of Health: R21EY029991, R01EY035679 NIH/NEI Center Support Grant: P30EY025580
We thank Nicholas Pomernackas for contributions to mouse husbandry, Dr. Kai Wang for statistical advice, and Brian Westra of the University of Iowa Libraries for assistance with data sharing and curation via Iowa Research Online. This work was supported by the National Institutes of Health (R21EY029991, R01EY035679) and a Grant-in-Aid from The Glaucoma Foundation. We also acknowledge an NIH/NEI Center Support Grant to the University of Iowa (P30EY025580) . The contents do not represent the views of the U.S. Department of Veterans Affairs or the U.S. Government.
- Language
- English
- Date published
- 10/2024
- Academic Unit
- Molecular Physiology and Biophysics; Ophthalmology and Visual Sciences
- Record Identifier
- 9984696864902771
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