W1206R mutation in mouse factor H causes retinal thrombosis and ischemic retinopathy

Abstract

Purpose : Factor H (fH) is an inhibitor of the complement cascade. SNP changes or rare mutations in fH are associated with age-related macular degeneration (AMD) and atypical hemolytic uremic syndrome (aHUS), which is a form of thrombotic microangiopathy. To generate a mouse model of aHUS, we created a point mutation (W1206R) in the mouse fH gene, mirroring a human aHUS-associated mutation. The mutant mice exhibited pathological features similar to human aHUS and had thrombosis in multiple organs including the retina; here we characterize the retinal manifestations.

Methods : Mice with a W1206R mutation (fH^R/R) were generated using a gene targeting approach. Fundus imaging and fluorescein angiography (FA) were performed to assess retinal appearance and perfusion in fH^R/R, heterozygous (fH^W/R) and wild-type control mice (fH^W/W) at age 10 wks. After euthanasia, eyes were processed for histology. Immunostaining with complement component 3 and fibrin were performed on cryo-preserved sections.

Results : Fundus images showed retinal artery occlusion, retinal vein dilation, cotton wool spot-like lesions, and hypopigmented spots in FH^R/R but not FH^W/R and FH^W/W mice (Fig 1A and B). FA demonstrated significantly delayed perfusion and widespread hypoperfusion in FH^R/R mice compared to other genotypes (Fig 1C and D). Thinning and effacement of the inner retina, dilated retinal veins (Fig 2A and B), undulation of photoreceptor nuclear layer and inner/outer segments, and RPE vacuolar degeneration (Fig 2C and D) were observed in FH^R/R mice. There was strikingly more C3 immunolabeling in Bruch’s membrane and fibrin immunolabeling in the retinal vasculature in FH^R/R mice than other genotypes.

Conclusions : Our results indicate that the W1206R mutation of the mouse fH gene leads to retinal thrombosis and ischemic retinopathy, as well as sub-RPE deposits. They suggest that complement dysregulation could contribute to thrombotic disorders in the retina. This mouse line can serve as a model of retinal vascular occlusion.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

 

Fundus images showed retinal artery occlusion, retinal vein dilation, cotton wool spot-like lesions, and hypopigmented spots in mutant mice (A and B). Fluorescein angiography showed delayed perfusion and widespread hypoperfusion in mutant mice (C and D).

 

Photomicrographs of plastic sections of mouse retinas showing ischemic retinopathy in mutant mice (B and D).