Autosomal recessive retinitis pigmentosa E150K opsin mice exhibit photoreceptor disorganization
Ning Zhang, … , Vladimir J. Kefalov, Krzysztof Palczewski
Ning Zhang, … , Vladimir J. Kefalov, Krzysztof Palczewski
Published December 10, 2012
Citation Information: J Clin Invest. 2013;123(1):121-137. https://doi.org/10.1172/JCI66176.
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Research Article Ophthalmology

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 higher-order 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.

Authors

Ning Zhang, Alexander V. Kolesnikov, Beata Jastrzebska, Debarshi Mustafi, Osamu Sawada, Tadao Maeda, Christel Genoud, Andreas Engel, Vladimir J. Kefalov, Krzysztof Palczewski

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Figure 2

E150K knock-in mice undergo progressive retinal degeneration.

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E150K knock-in mice undergo progressive retinal degeneration. (A) Repres...
(A) Representative 3D OCT images of 2-month-old WT and KK retinas. Scale bar: 20 μm. The ONL was substantially thinner in retinas of KK mice. (B) Thicknesses of the ONL measured 500 μm from the optic nerve head in nasal OCT images of genetically different mice as shown at various ages (n > 3). KK mice evidenced photoreceptor degeneration by 1 month of age and had lost almost all their photoreceptors at the age of 4 months. (C) Plastic sections of retinas stained with toluidine blue from WT, EK, and KK mice at 1 and 4 months of age. EK retina displayed an intermediate progression of retinal degeneration indicated by modest degeneration by 4 months of age that progressed to nearly complete loss of photoreceptors by 10 months of age. (D) Numbers of nuclei per column in the superior-inferior and nasal-temporal axis of plastic sections crossing the optic nerve head in genetically different mice at 2 months of age (n = 3). WT and EK mouse retinas exhibited virtually identical numbers of nucleated photoreceptor cells, whereas there was substantial loss of photoreceptors in KK retina. No notable regional differences in degeneration were observed in KK retina. OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer.