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Heather Schmitt, TeddiJo Watkins, Kristyn Hake, Megan Kuhn, Guorong Li, Daniel W Stamer, Michael A Hauser; Genetic susceptibility to Loxl1 knockout-induced elastosis in a mouse model. Invest. Ophthalmol. Vis. Sci. 2021;62(8):468.
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Pseudoexfoliation glaucoma (PEXG) is an ocular manifestation of the systemic elastotic disease pseudoexfoliation syndrome (PEX), and can be diagnosed by fibrillary deposits in the anterior chamber and significantly increased intraocular pressure (IOP). PEX-related extracellular matrix dysregulation can manifest as pelvic organ prolapse, inguinal hernia, aortic aneurism, or COPD. Consistent with these pathologies, polymorphisms in the lysyl oxidase-like 1 (LOXL1) gene, which codes for an elastin crosslinking and assembly enzyme, impart significant risk for PEX. Thus, changes in LOXL1 expression may lead to elevated IOP in PEXG, as the outflow tissues that regulate IOP are highly elastic. Here, we use a Loxl1 knockout mouse model to investigate genetic susceptibility to the elastotic phenotypes associated with Loxl1 depletion.
129S.C57Bl/6.Loxl1+/- mice were backcrossed onto the C57Bl/6 background for 6 generations (N6). Two month old N6 and mixed background 129S/N6 (N1) Loxl1+/+, +/- and -/- mice were analyzed for systemic phenotypes including anal prolapse, skin elasticity, total weight, and morphological changes in major organs. Ocular phenotypes monitored include IOPs and histology of anterior and posterior segments.
Prolapse prevalence was significantly higher in N6 C57Bl/6 mice in comparison to mixed background mice (p<0.0001). In mixed 129S/N6 (N1) Loxl1-/- mice, significant increases in skin tiring (p=0.0235) and reduction in elastic recovery (p=0.0294) were observed. The tiring effects of skin after repeated stretch were significantly higher in Loxl1-/- animals versus Loxl1+/+ and +/- littermates (p=0.0010). Knockout of Loxl1 in the N6 C57Bl/6 mice led to significant weight loss (p<0.05), and systemic and ocular tissues exhibited enlarged luminal spaces histologically. Knockout of Loxl1 in mixed background mice lead to significantly increased IOP (p<0.0001), but no significant IOP increase was observed in the N6 C57Bl/6 mice.
Genetic background significantly affects the systemic and ocular phenotypes of elastosis associated with Loxl1 knockout. This data shows for the first time that susceptibility to Loxl1 knockout-induced elastosis depends upon genetic modifiers that may contribute to phenotypic severity of PEX, providing a foundation for studying gene targets associated with this susceptibility that are relevant in human patients.
This is a 2021 ARVO Annual Meeting abstract.
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