Abstract
Q344ter is a naturally occurring rhodopsin mutation in humans that causes autosomal dominant retinal degeneration through mechanisms that are not fully understood, but are thought to involve an early termination that removed the trafficking signal, QVAPA, leading to its mislocalization in the rod photoreceptor cell. To better understand the disease mechanism(s), transgenic mice that express Q344ter were generated and crossed with rhodopsin knockout mice. Dark-reared Q344terrho+/− mice exhibited retinal degeneration, demonstrating that rhodopsin mislocalization caused photoreceptor cell death. This degeneration is exacerbated by light-exposure and is correlated with the activation of transducin as well as other G-protein signaling pathways. We observed numerous sub-micrometer sized vesicles in the inter-photoreceptor space of Q344terrho+/− and Q344terrho−/− retinas, similar to that seen in another rhodopsin mutant, P347S. Whereas light microscopy failed to reveal outer segment structures in Q344terrho−/− rods, shortened and disorganized rod outer segment structures were visible using electron microscopy. Thus, some Q344ter molecules trafficked to the outer segment and formed disc structures, albeit inefficiently, in the absence of full length wildtype rhodopsin. These findings helped to establish the in vivo role of the QVAPA domain as well as the pathways leading to Q344ter-induced retinal degeneration.
Highlights
Retinitis pigmentosa (RP) comprises a group of inherited retinal disorders characterized by initial night blindness and a progressive loss of peripheral vision which eventually compromises visual acuity and culminates into total blindness
Almost the entire amplified PCR product from the Q344terrho2/2 retinas was cleaved by AvrII, while a proportion of the total PCR product from Q344terrho+/2 samples was cleaved by AvrII, and none was cleaved in the transgene-negative samples (Fig. 1C)
Such novel signaling pathway(s) may contribute to light-induced retinal degeneration in these mice. In this investigation we utilized transgenic Q344ter mice to gain a better understanding of the pathways that contribute to retinal degeneration in ADRP patients inheriting this rod opsin mutation
Summary
Retinitis pigmentosa (RP) comprises a group of inherited retinal disorders characterized by initial night blindness and a progressive loss of peripheral vision which eventually compromises visual acuity and culminates into total blindness. In most cases RP is initiated by the death of rod photoreceptors, its progression eventually affects cones, leading to total vision loss. Class II mutants have characteristics distinct from WT rhodopsin: their expression levels were markedly lowered; they failed to or poorly regenerated with 11-cis retinal; and in varying degrees they were retained in the endoplasmic reticulum (ER). These empirical properties were attributed to protein mis-folding [6,7,8,9]
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