Update on Animal Models of Exfoliation Syndrome

Abstract

Animal models are powerful tools for studying diseases that affect the eye, such as exfoliation syndrome (XFS). Two types of animal models have been used to investigate the pathophysiology of XFS and glaucoma. One class of models is engineered to have key features of a disease by alteration of their genome (genotype-driven animal models). LOXL1 is the first gene known to increase the risk for developing XFS in humans. Two transgenic mouse models with altered Loxl1 genes have been generated to study XFS. One strain of mice, Loxl1 deficient mice, also known as Loxl1 knockout mice, have had the Loxl1 gene removed from their genomes. Another strain has been engineered to produce excess amounts of the protein produced by the Loxl1 gene, or Loxl1 overexpression. A second class of animal models includes naturally occurring strains of mice that exhibit key clinical features of a disease. Studies of these phenotype-driven animal models may identify genes that cause disease and may also provide a valuable resource for investigating pathogenesis. One strain of mice, B6-Lyst, has several key features of human XFS, including ocular production of exfoliation-like material, and stereotypical iris abnormalities. Studies of this range of mice and other public mouse genetic resources have provided some important insights into the biology of XFS and may be useful for future studies to test the efficacy of drug therapies.

Figure 1. Ocular examination of mice for signs of exfoliation syndrome and glaucoma

Most examination techniques for human eyes can be employed to study mouse eyes (setup, left column; resultant data, right column). (A) Slit-lamp examination of a dilated eye with broad-beam illumination is a primary tool that can be used to screen for exfoliation syndrome in mice. Mice with overt deposits of exfoliative material in the anterior chamber have not yet been discovered; the expectation is that exfoliative material would most likely be present in a “bulls-eye” pattern on the lens. Pigment accumulation in the inferior angle would likely also be observable. Wild-type C57BL/6J eye pictured. (B) Concentric iris transillumination can be detected in affected eyes by shining a beam of light through an undilated pupil, as seen in the eyes of B6-Lyst^bg-J mice shown here. (C) Gonioscopy is used to visualize the iridocorneal angle and can be used to screen for the presence of exfoliative material and liberated pigment (arrowheads), as seen in the eyes of B6-Lyst^bg-J mice shown here. (D) Rebound tonometry is used to assess intraocular pressure of mice; compared to strain- and age-matched controls, mice with secondary glaucoma would be expected to have an elevated intraocular pressure (E) Retinal optical coherence tomography can identify thinning of the retinal ganglion cell complex (optically dense retinal layer between red lines with accompanying arrowheads) in glaucomatous eyes. Wild-type retina shown.

Figure 2. Human and mouse LOXL1 genomic locus

The LOXL1 locus displayed on the RefSeq genes track of the UCSC genome browser for (A) human genome build hg38 and (B) mouse genome build mm10 indicate that LOXL1-AS1 is a human-specific gene. Note that the human and mouse genes are transcribed in opposite directions.

Figure 3. The B6-Lyst^bg-J mouse has altered pigmentation

The most striking feature of the B6-Lyst^bg-J mouse is its beige coat color, which differentiates it from its parental C57BL/6J strain, which has a black coat color.