This is a pilot study looking at three disease genes for Leber Congenital Amaurosis, early onset Retinitis Pigmentosia (RP) and Cone-Rod Dystrophy (CRD), and the likelihood that these genes govern human retinal functions that can be evaluated by appropriate tests. The three genes are CRX, which is involved in opsin expression and photoreceptor differentiation; expressed in the photoreceptor; RetGC, Retinal Guanylyl Cyclase; also expressed in the photoreceptors; RPE65, expressed in the retinal pigment epithelium, possibly the isomerase in the visual cycle. Mutations of CRX are predicted to cause deficient opsin expression with consequent deficiencies in the visual pigment rhodopsin, shortening of the photorecptor outer segments, low photocurrent, reductions in the photoreceptor and visual sensitivity that are proportional to the amount of the visual pigment present. These predictions can be tested with a combination of electroretinographic and psychophysical procedures, such as measurements of threshold during dark adaptation. The protein of RetGC is guanylyl cyclase. Cyclic GMP channels in the photoreceptor outer segments are open in the dark, and close in response to light. The cyclase resynthesizes cGMP. The investigators predict abnormalities in the cyclase will alter the kinetics of recovery of the photoreceptors' photocurrent with consequent alterations in retinal adaptation, that is the adjustment to light and dark. This can be tested by studies of dark adaptation and ERG assessment of the kinetics of recovery of the photoreceptors' response to light. RPE65 is expressed in the pigment epithelium, and is involved in metabolism of retinoids. Possibly the protein is the isomerase in the visual cycle. This enzyme converts all trans to the 11-cis form of retinaldehyde which is bound to opsin to form the visual pigment in the photoreceptor outer segments. The visual pigment catches light and starts the processes that result in vision. The investigators hypothesize that RPE65, by alterations in isomerase (or closely related enzymes), alter the kinetics of recovery of the photoreceptor's sensitivity and visual sensitivity after exposure to light. This prediction can be tested by using a combination of tests of vision and retinal function that employ electroretinographic and psychophysical procedures. The above hypotheses will be tested in individuals who are obligate heterozygotes for LCA and the related conditions. These individuals are the parents of affected children. The affected children have severe visual impairment and nystagmus which limits the possibility of testing the hypotheses in them.
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