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MinHee K. Ko, Jose Gonzalez, James C Tan; Glaucoma features in a fibrillin-1 mutant mouse. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2556.
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© ARVO (1962-2015); The Authors (2016-present)
Risk factors associated with retinal ganglion cell (RGC) loss in human primary open angle glaucoma (POAG) are increasing age, thinner central corneas, and intraocular pressure (IOP). Epidemiological studies reveal that between 30-92% of people with POAG have IOP indistinguishable from normal. We describe features resembling glaucoma in the tight skin (Tsk) fibrillin-1 mutant mouse.
IOP (rebound tonometry) and central corneal thickness (CCT, OCT) were measured in live Tsk mice in different aged groups. In enucleated Tsk eyes, RGC (BRN3a) and optic nerve axon (p-phenylenediamine) counts, the presence of RGC apoptosis (Annexin V) and glial reactivity (GFAP) were analyzed by immunohistochemistry. Tsk findings were compared with those of age-matched wild-type (WT) mice (C57BL/6).
At 3-6 months (m) of age, Tsk mean IOP was 28% lower than WT IOP (p<0.0002). Tsk mean IOP in 7-10m had risen 22% more than those of Tsk in 3-6m, which become indistinguishable (p=0.7) from age-matched WT IOP. Tsk mean IOP and WT IOP remained unchanged (p=0.1) over the same period. IOP in 10% of Tsk eyes exceeded the 97.5th centile for age-matched WT IOP. Fellow eyes with higher and lower IOP were analyzed separately by linear regression for age-related trends. Tsk eyes with higher IOP (p=0.001; rate 0.5mmHg/m) and lower IOP (p=0.003; rate 0.3mmHg/m) showed a trend of increasing IOP with age. Similar analysis of WT IOP over the same age range did now show any change (p=0.1). Tsk CCT was 20% less than age-matched WT CCT (p=0.00001). This relative difference did not change with age. RGC counts were lower in Tsk mice aged 7-10m than 3-6m (by 28%; p=0.03), but WT RGC counts did not decline with age. At 7-10m of age, RGC counts in Tsk eyes were 33% less than WT. Evidence of increased apoptosis and glial activation was seen in the ganglion cell layer of Tsk compared with WT retina.
We found evidence in Tsk mice of increasing IOP and RGC attrition with age. Despite thinner Tsk central corneas, IOP above WT normal limits was detectable in 10%. These mouse ocular features resemble the human POAG phenotype and indicate that further studies of the Tsk fibrillin-1 mutant could shed light on this important eye disease.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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