Autosomal recessive retinitis pigmentosa E150K opsin mice exhibit photoreceptor disorganization

Abstract

The pathophysiology of the E150K mutation in the rod opsin gene associated with autosomal recessive retinitis pigmentosa (arRP) has yet to be determined. We generated knock-in mice carrying a single nucleotide change in exon 2 of the rod opsin gene resulting in the E150K mutation. This novel mouse model displayed severe retinal degeneration affecting rhodopsin's stabilization of rod outer segments (ROS). Homozygous E150K (KK) mice exhibited early-onset retinal degeneration, with disorganized ROS structures, autofluorescent deposits in the subretinal space, and aberrant photoreceptor phagocytosis. Heterozygous (EK) mice displayed a delayed-onset milder retinal degeneration. Further, mutant receptors were mislocalized to the inner segments and perinuclear region. Though KK mouse rods displayed markedly decreased phototransduction, biochemical studies of the mutant rhodopsin revealed only minimally affected chromophore binding and G protein activation. Ablation of the chromophore by crossing KK mice with mice lacking the critical visual cycle protein LRAT slowed retinal degeneration, whereas blocking phototransduction by crossing KK mice with GNAT1-deficient mice slightly accelerated this process. This study highlights the importance of proper higherorder organization of rhodopsin in the native tissue and provides information about the signaling properties of this mutant rhodopsin. Additionally, these results suggest that patients heterozygous for the E150K mutation should be periodically reevaluated for delayed-onset retinal degeneration.

Nanodomain organization of rhodopsin in native human and murine rod outer segment disc membranes

“…The similarities in the properties of human and murine nanodomains indicate that factors contributing to the formation of nanodomains are conserved and that murine ROS disc membranes can serve as a good model for understanding the organization of human rhodopsin in ROS disc membranes. Additionally, the availability of different animal models will allow the testing of whether pathological conditions can alter the normal organization of rhodopsin in the ROS disc membrane and provide insights into the detrimental effects that may follow (e.g., [87, 88]). Although rhodopsin is unique among GPCRs in that it is expressed at high concentrations and purity in ROS disc membranes, the organization of receptors into nanodomains may be a common feature among GPCRs [89].…”

DICER1 is essential for survival of postmitotic rod photoreceptor cells in mice

“…Whole‐animal ERG recordings were performed as described previously (33, 36). Transretinal ERG recordings also were performed as published previously (37).…”

Molecular pharmacodynamics of emixustat in protection against retinal degeneration

“…The development of retinal degeneration was then examined by ultra-high-resolution spectral domain OCT (SD-OCT; Bioptigen) and ERG as previously described (10,70). Analysis of emixustat amides in mouse eyes.…”