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P. Krajacic, Y. Qian, P. Hahn, T. Dentchev, N. Lukinova, J.L. Dunaief; Retinal Localization and Copper Dependent Re–Localization of the Wilson and Menkes Disease Proteins . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2892.
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Menkes and Wilson diseases are both associated with neurodegeneration and retinal degeneration. The Menkes and Wilson genes are homologous copper transporters, but differences in their expression pattern leads to different clinical manifestations. The Menkes gene is expressed in the gut and blood–brain–barrier, with mutations leading to systemic and CNS copper deficiency. Conversely, the Wilson gene is expressed predominantly in the liver, the main route of copper elimination, with mutations leading to hepatic, systemic and CNS copper overload. The retinopathy in both diseases could result from abnormal systemic copper levels and/or from loss of retinal Wilson and Menkes protein functions. To determine whether the Wilson and Menkes genes may act locally in the retina, this study was undertaken to assess retinal Wilson and Menkes expression and localization.
RT/PCR was used to test for the presence of Wilson and Menkes mRNAs mouse and human retinas and retinal pigment epithelial cell lines. The Menkes and Wilson proteins were immunolocalized in human and mouse retinas. The Wilson protein was immunolocalized in ARPE–19 cells in the presence of normal and high copper concentration in the medium.
Both the Menkes and Wilson mRNA and protein were present in the RPE, but only the Menkes mRNA was detected in the neurosensory retina. The Menkes protein immunolocalized to the RPE, outer plexiform layer and ganglion cell layer. The Wilson protein immunolocalized only to the RPE. Within the RPE, both the Wilson and Menkes protein localized to the golgi. Increased copper concentration in vitro led to re–localization of the Wilson protein away from the golgi to a more diffuse cytoplasmic distribution.
Both the Menkes and Wilson proteins are present in the RPE. Since the RPE is a blood–brain–barrier, these proteins likely regulate not only their own copper levels but also copper levels of the overlying photoreceptors. Since the Wilson protein delivers copper to the ferroxidase ceruloplasmin in the liver, it is likely that the Wilson protein provides copper to ceruloplasmin made in the RPE. Retinopathy in Wilson and Menkes disease may result not only from abnormal systemic copper levels but also from loss of retinal Wilson or Menkes protein.
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