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 10

Effects of genetic depletion of 11-cis-retinal production or absence of rod phototransduction on retinal degeneration in KK mice.

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Effects of genetic depletion of 11-cis-retinal production or absence of ...
(A) Plastic sections of retinas crossing the optic nerve head of 2-month-old KK and KKLrat–/– mice. Sections were stained with toluidine blue (upper panels). KKLrat–/– retina showed increased number of rows of photoreceptor cell nuclei as compared with age-matched KK retina. This finding is consistent with the increased thickness of the ONL in KKLrat–/– retina shown in the corresponding SD-OCT images (lower panels). (B) Thickness of the ONL in KK, KKLrat–/–, and Lrat–/– mice measured at 500 μm from the optic nerve head of nasal OCT images (n > 3). Depletion of 11-cis-retinal partially protected against retinal degeneration in KK mice. (C) SD-OCT images of retinas crossing the optic nerve head from 1-month-old KK and KKGnat1–/– mice. KKGnat1–/– retina displayed decreased thickness of ONL relative to an age-matched KK retina. (D) Thickness of the ONL in KK, KKGnat1–/–, and Gnat1–/– mice measured 500 μm from the optic nerve head in nasal OCT images (n > 3). Absence of the Gtα caused greater retinal degeneration in KK mice. *P < 0.05, **P < 0.01. Scale bars: 20 μm.