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J. Gnana, P.M. Martin, S.B. Smith, V. Ganapathy; Expression of HFE and Other Hemochromatosis Genes in Mouse Retina . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2061.
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Hereditary hemochromatosis (HH) is a genetic, autosomal recessive, disorder of iron overload leading to oxidative stress in various tissues and a myriad of clinical symptoms such as diabetes, cardiomyopathy, arthritis, liver cirrhosis, and hypogonadism. Recent studies have shown that increased iron accumulation in RPE, resulting from the combined disruption of the function of two iron regulatory proteins, ceruloplasmin and hephaestin, leads to retinal degeneration with characteristics similar to those of age–related macular degeneration (AMD). Therefore, we predicted that HH would be associated with iron overload in retina. Disruption of HFE function, (a Histocompatability leukocyte antigen class I–like protein involved in iron (FE) homeostasis) due to a mutation in the gene is responsible for ∼90% of cases with HH. HFE expression in retina has not been studied. Therefore, we analyzed the expression and localization of HFE with respect to other hemochromatosis related genes in normal mouse retina.
HFE was localized in intact retina by in situ hybridization and immunohistochemistry. RT– PCR was done to detect the expression of HFE mRNA in neural retina and RPE/eyecup. The expression pattern of other hemochromatosis related genes was also analyzed using similar techniques.
In situ hybridization for the analysis of HFE mRNA and immunofluorescence for the analysis of HFE protein revealed that HFE is expressed in the retina and that the expression is restricted exclusively to the RPE. The protein shows a polarized distribution in RPE, being localized predominantly in the basolateral membrane of the cell. RT–PCR analysis of normal retina showed predominant expression of HFE in RPE/eyecup confirming the results. Expression of other hemochromatosis related genes, TfR1, TfR2 and ß2–microglobulin was also evident in the retina; but, unlike HFE, the expression of these other genes is not restricted to RPE but is widespread in various cell layers.
HFE expression in RPE indicates its essential role in the regulation of iron homeostasis in retina. The basal membrane of RPE, which is in contact with choroidal blood, is the site of first step in the cellular uptake of iron from blood. Therefore, the specific location of HFE and its related proteins, TfR1 and TfR2 in the basolateral membrane of this cell layer is of physiologic significance. Patients with hemochromatosis are likely to have disrupted iron homeostasis in the retina, which might contribute to age–related RPE dysfunction and retinal degeneration as seen in AMD.
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