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Rick N. Nordgren, Philip Sommer, Adam M. Dubis, Jungtae Rha, Maureen Neitz, Thomas B. Connor, Jr., Jay Neitz, Joseph Carroll; Involvement of L/M Opsin Polymorphisms in Cone Dystrophy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4895.
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To understand the cellular and molecular basis of a cone dystrophy associated with a congenital red-green color vision defect. A 32-year-old man was diagnosed with color blindness and progressive vision loss beginning in grade school that has stabilized over the past few years. Previous testing showed subnormal photopic ERG oscillatory potentials and normal dark-adapted psychophysical thresholds.
Retinal images were obtained using SD-OCT (Bioptigen, Inc. & Carl Zeiss Meditec, Inc.). High-resolution images of the photoreceptor mosaic were obtained using a high-speed, flood-illuminated, adaptive optics ophthalmoscope. DNA was extracted from whole blood and the L/M gene array was analyzed.
The subject’s best corrected visual acuity was 20/125 OU and a fundus exam showed subtle RPE stippling in an annular pattern around the fovea. SD-OCT images showed significant macular thinning and a focal disruption of the IS/OS junction at the fovea. The ONL layer was reduced in thickness compared to normal. Adaptive optics images of the photoreceptor mosaic revealed a sparse array of cones in the fovea, presumably representing S-cones. In the periphery we observed a nearly continuous mosaic of rod photoreceptors interrupted by numerous cone inner segments; reminiscent of what has been reported for achromatopsia and blue-cone monochromacy (BCM). The genetic analysis revealed a single L/M opsin gene; the amino acids at the dimorphic positions in exon 3 were, leucine 153, valine 171, alanine 174, valine 178, and alanine 180 (LVAVA), a combination never seen in males with normal vision.
The subject's congenital red-green color vision deficiency is explained by deletion of all but one of his X-chromosome opsin genes. The LVAVA opsin encoded by the one X-linked gene is presumably expressed in all but S cones. The abnormal amino combination appears to cause a progressive loss of cone function, leaving only S cones intact and healthy in this 32 year old, explaining the anatomical similarities to BCM. A review of our database revealed two additional subjects with the LVAVA combination and dichromatic color vision, and they also were diagnosed with cone dystrophy, suggesting that this "two-hit" mechanism may be a more general explanation for certain individuals diagnosed with cone dystrophy.
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