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James A. Kuchenbecker, Scott H. Greenwald, Joseph Carroll, Gerald A. Fishman, Mohamed A. Genead, Thomas B. Connor, Jr., Maureen Neitz, Jay Neitz; Cone Isolating Electroretinograms In Individuals With A Mutant Opsin Allele Associated With Cone Dystrophy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6400.
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To record full-field ON-OFF cone-isolating electroretinograms (ERGs) from affected males to evaluate the effects of an LVAVA opsin variant on cone function. LVAVA opsin is a chimera of the long (L) and middle (M) wavelength opsins. Such "L/M interchange mutants" are not observed in Old World, non-human primates. They presumably arose in humans by the relaxation of selection against opsin mutations that occurred through meiotic recombination that intermixed ancestral L and M sequences. This particular L/M interchange mutant, designated LVAVA to indicate the amino acids encoded at positions 153, 171, 174, 178 and 180, has recently been found to underlie a cone-type specific dystrophy.
Subjects were two unrelated males diagnosed with cone dystrophy. Both males had been shown previously to have a single X-chromosome cone opsin gene, and in each case the gene encoded an LVAVA variant. For one male the LVAVA variant was specified by an OPN1LW gene, and for the other it was specified by an OPN1MW gene. In both cases, imaging results were indistinguishable from blue-cone monochromats where mutations, such as LCR deletions, cause an early complete loss of functional cones expressing the mutant. Here we evaluated visual acuity and color vision, and recorded ON-OFF long-flash chromatic ERGs under cone isolating conditions to evaluate function of cones expressing an LVAVA opsin variant.
Each subject demonstrated residual color vision. Visual acuity was 20/100 to 20/200. Each subject had an L/M-cone ERG amplitude of approximately 5-10% compared to a normal control. To ensure the ERG waveform was not S-cone or rod mediated, an intensity response series was recorded using long wavelength (640nm) light. At this wavelength, the sensitivity of S-cones and rods is reduced by 7 and 4 log units, respectively, thus we are confident there was no S-cone or rod contamination.
LVAVA is associated with severely reduced visual acuity. However, color vision behavior and ERG results indicate that at least some cones containing an LVAVA opsin variant are intact and respond to light. Our data, taken together with previous retinal imaging data on these subjects, indicate that the cone-specific dystrophy does not result in complete loss of photoreceptor structure or function which may make it amenable to gene-mediated therapy.
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