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C. M. Maurer, H. B. Schoenthaler, S. C. F. Neuhauss; A Mutation in Pyrvate Dehydrogenase Leads to Reduced Vision in the Zebrafish Noir Mutant. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5180.
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Large-scale mutagenesis screens have been performed in the zebrafish, Danio rerio, to identify genes involved in the function of the visual system.In such a screen the mutant noir has been identified due to its dark external appearance. This phenotype results from a lack of background adaptation, which indicates an impaired visual ability. The reduced vision was confirmed by electroretinography which revealed a block of signal transduction from primary to secondary neurons starting at 5 days postfertilization (dpf) reflected in a negative ERG. Further recordings at 7 dpf revealed a defect in the outer retina at this stage.
By linkage analysis and positional cloning the mutation has been mapped. Morphological integrity of the retina was examined by standard histology, transmission electron microscopy and immunohistochemical stainings. Moreover, the electrophysiological properties of mutant and wild type retinas were analyzed by ERG recordings. Expression patterns of genes of interest have been examined by in situ hybridization.
Mapping of the mutation revealed that a defect in a subunit of the Pyruvate Dehydrogenase complex underlies the noir mutant phenotype. Malfunction of this enzyme leads to the ablation of the ERG b-wave at 5 dpf and to a complete lack of both, a- and b-wave at 7 dpf. At 6 dpf defects in the inner nuclear layer are observed in histological sections of the retina. This defect extends to the outer retina at 7dpf. We could not see an increase in apoptosis, therefore we hypothesize that abnormal in-growth of blood vessels could account for the morphological alterations observed in the inner nuclear layer. Interestingly, a ketogenic diet consisting of long-chain fatty acids could rescue the noir mutant phenotype. Mutant larvae survived longer and the ERG and histological phenotype were significantly improved. The long-chain fatty acids provide an alternative energy source to restore diminished acetyl-CoA levels caused by the block linking glycolysis and Krebs cycle.Future work will include the analysis of metabolite levels to detect potentially toxic effects of accumulated metabolites and their impact on retinal cells.
A mutation in a metabolic key enzyme leads to a reduced vision and retinal dystrophy in the zebrafish noir mutant. The defect initiates in the inner nuclear layer and expands to the photoreceptor layer, suggesting a more complex pathogenesis than simple energy deprivation.
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