Electroretinographic abnormalities in parents of patients with leber congenital amaurosis who have heterozygous GUCY2D mutations

Background: Leber congenital amaurosis (LCA) is an infrequently encountered congenital form of retinitis pigmentosa with marked genetic and clinical heterogeneity. Thus far, 10 genes have been identified in this disorder since 1996. In the future, LCA may become treatable by gene and/or pharmacological intervention, and these therapies will likely be gene specific, giving major significance to rapid gene identification and genephenotype studies. Objective: To test the hypothesis that parents of patients with LCA have identifiable electroretinographic and psychophysical changes. Subjects, Materials, and Methods: Complete eye examinations and electroretinographic studies were performed on 2 sets of parents whose offspring were diagnosed as having LCA and who were found to carry a mutation in 1 of the 10 LCA genes - GUCY2D. One set of parents also underwent static perimetry threshold measurements. Results: We found that single flash-light-adapted a- and b-wave amplitudes, 30-Hz flicker, or both cone signals were significantly decreased in amplitude in 4 heterozygotes, while 2 parents showed delayed 30-Hz flicker implicit times. Electroretinographic rod-mediated signals were normal in 2 of the heterozygotes, but subnormal in 2. Static perimetry testing showed normal thresholds in the 2 heterozygotes tested. Main Outcome Measures: Single flash-light-adapted a- and b- wave amplitudes and implicit times, 30- or 32-Hz flicker amplitudes and implicit times, rod-mediated signals, and dark-adapted, rod-mediated thresholds. Conclusions: Some carrier parents of patients with LCA and a GUCY2D mutation develop measurable, cone and possibly rod abnormalities most consistent with a mild conerod dysfunction. This correlates well with the known retinal expression pattern of GUCY2D, which is considerably higher in cone compared with rod photoreceptor cells

The impact of genetic background on neurodegeneration and behavior in seizured mice

We used pilocarpine-induced seizures in mice to determine the impact of genetic background on the vulnerability of hippocampal neurons and associated changes of behavioral performance. The susceptibility of hippocampal neurons to seizure-induced cell death paralleled the severity of the seizures and depended on genetic background. Hippocampal neurons in C57BL/6 mice were most resistant to cell death, whereas they were highly vulnerable in FVB/N mice. The degree of neuronal degeneration in F1 hybrid mice obtained by crossing the two strains was at an intermediate level between the parent strains. Two weeks after the severe seizures, performance in a water-maze place navigation task showed a bimodal distribution. Seventeen of 19 (90%) F1 mice were completely unable to learn while the other two learned reasonably well. Of 28 C57BL/6 mice with similarly severe seizures, six were as strongly impaired as their F1 counterparts (22%). The remaining 22 performed normally, indicating a much lower probability of C57BL/6 mice to be affected. Treated mice showed a deficit of open-field exploration which was strongly correlated with the impairment in the place navigation task and was again more severe in F1 mice. Our results show that the vulnerability of hippocampal neurons to pilocarpine-induced seizures, as well as the associated behavioral changes, depended on genetic background. Furthermore, they confirm and extend our earlier finding that a relatively modest reduction of hippocampal cell death can be associated with dramatic changes of behavioral performance and emphasize the importance of tightly-controlled genetic backgrounds in biological studies