Abstract
Purpose :
PRPH2 mutations cause a broad range of autosomal dominant retinal degenerations; however, the basis for variable disease phenotype and penetrance, and the drivers of pathophysiology are not well understood. PRPH2 encodes peripherin-2, an integral membrane tetraspanin that scaffolds photoreceptor outer segment (OS) disk rim structure. We previously found that a prph2Y285x/+ nonsense mutation, associated with cases of human pattern dystrophy, reduced murine scotopic ERG a-wave but not b-wave amplitudes in young mice. The present study investigates how aging affects retinal function and structure in prph2Y285x/+ mice to better understand progressive disease pathophysiology and progression.
Methods :
A previously established line of prph2Y285x/+ knock-in mice were characterized relative to littermate prph2+/+ controls. Phenotyping assays included: H&E histology, in vivo full-field ERG, transretinal ex vivo ERG, immunofluorescence microscopy, and transmission electron microscopy.
Results :
P21 prph2Y285x/+ disease model mice possess near-normal numbers of rod and cone photoreceptors, and IS-OS layers of normal thickness, but OSs with abnormal ultrastructure (relative to WT). In vivo ERGs recorded under scotopic conditions revealed that the structurally abnormal rods generated significantly attenuated (>2-fold reduced) a-waves, but left b-waves unaffected. Ex vivo scotopic ERG recordings likewise showed a relative insensitivity of rod b-waves, despite reduced a-wave amplitudes. Furthermore, ex vivo photopic recordings showed that, despite significantly attenuated cone a-wave responses, b-waves of normal amplitudes were preserved. Follow-up studies using in vivo ERG showed that the functional (b-wave) compensation present at P21 was lost on a time-scale of several weeks, prior to substantial photoreceptor cell loss or tissue-level changes.
Conclusions :
Pre-degenerative retinas of prph2Y285x/+ mice show a robust functional compensation, in which b-wave responses are partially or fully preserved despite significantly reduced a-waves. Because this compensation occurs prior to the appearance of major degenerative changes, it may reflect altered signaling properties of rod and cone photoreceptors induced by abnormal OS structures. The findings introduce the possibility that a novel form of homeostatic compensation may also apply to cases of human retinal disease associated with PRPH2 mutations.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.