Abstract
Purpose :
Exfoliation syndrome (XFS) is a systemic connective tissue disorder. Though the mechanism is unknown, Loxl1-/- mice recapitulate some mild ocular features of XFS, indicating lysyl oxidase like 1 (LOXL1 encoded by LOXL1) is involved in pathophysiology. We hypothesize elastic fiber defects caused by inadequate elastin crosslinking due to lack of LOXL1, combined with microfibril deficiency due to FBN1 mutation (encoding fibrillin-1, Fbn1C1041G/+), will display ocular and systemic phenotypes of XFS.
Methods :
Loxl1-/- (gift from Tiansen Li) was backcrossed to C57BL/6J background, then crossed with Fbn1C1041G/+ to create double mutant (dbm; Fbn1C1041G/+; Loxl1-/-) mice. Ocular features such as intraocular pressure (IOP) measured by tonometry, visual acuity (VA) measured by optomotor reflex, and biometry measured by optical coherence tomography (OCT) were characterized in 4 genotypes (wt, Fbn1C1041G/+, Loxl1-/-, dbm) at 4 months old. Optic nerves (ON) were fixed, and cross-section area measured by ImageJ. Phenotyping was performed in cardiovascular and pulmonary systems. Two-tailed student’s t-test was used for statistical analysis.
Results :
At 4 months old, there was no significant difference in IOP between the 4 genotypes. VA was significantly reduced only in dbm compared to wt. Majority of biometric parameters showed significant difference in all 3 mutant genotypes compared to wt, and dbm had exacerbated anomalies when compared to single mutants. Dbm ON areas were significantly larger when compared to age-matched wt (Figure 1). Cardiovascular phenotype revealed cardiomegaly and ascending aortic dilation in dbm (n=6, 0.13±0.03g, 1.1±0.1mm) compared to wt (n=5, 0.07±0.01g, 0.62±0.08mm, p=0.002 and p=0.0005, respectively). Histological examination showed fragmented elastin fibers of ascending aortic wall, multifocal leukocytoclastic aortitis, arteritis, and valvulopathy of both atrioventricular valves, and severe emphysema and bronchiectasis in the lungs of dbm mice.
Conclusions :
Ocular and systemic findings in dbm mice support interaction between fibrillin-1 and LOXL1, two prominent components of exfoliation material. Reduced VA in dbm could be due to refractive errors caused by biometric changes, and/or reduced retinal ganglion cell function by enlarged ON as shown previously. The systemic findings of dbm mice also provide insight on the link of XFS with cardiovascular and pulmonary diseases in humans.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.