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D.G. Brooks, T. Baradet, I. Devaux, C. Beaumont, D. Stambolian; A Transgenic Mouse Model of Hereditary Hyperferritinemia Cataract Syndrome: Implications for Protein Insolubility as a Mechanism of Cataract Formation . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3486.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Hereditary hyperferritinemia cataract syndrome (HHCS) is the paradigm of cataract formation resulting from crystallization of a native lens protein. Loss of protein solubility is an important cataractogenic mechanism and crystallization is the extreme of insolubility. Our goal was to develop and characterize a transgenic mouse model of HHCS to investigate lens ferritin insolubility and cataractogenesis. Methods: Three lines of transgenic mice were made by engineering a typical HHCS mutation into the normal mouse L-ferritin gene. Ferritin was quantitated by ELISA and detected by immunohistochemistry with monospecific anti-mouse-L-ferritin antibodies. Results: All three lines of mice over express mouse L-ferritin 5-20 fold in all tissues examined including lens and serum. L-ferritin antigen is only detectable by immunochemistry in lens epithelial cells of transgenic, not control animals. Rare ferritin aggregates are found in lens, especially in cortical lens fibers. Extracellular ferritin aggregates are observed that exhibit ordering into paracrystalline deposits or frank crystals. Crystalline ferritin is also observed in retina and extraocular tissues. In one line of mice, large ferritin inclusions are observed in the cytoplasm and nucleus of many tissues. In viscera, but not in the eye, there is significant stainable iron associated with these ferritin inclusions. Conclusions: Human HHCS features autosomal dominant inheritance of specific L-ferritin gene mutations, elevated serum ferritin and cataracts which are crystals of L-ferritin (IOVS 43: 1121, 2002). HHCS patients suffer progressive glare/photophobia from these light-diffracting crystalline cataracts. This transgenic mouse model recapitulates both the hyperferritinemia and cataract phenotype of HHCS. Over expressed mouse L-ferritin accumulates and forms aggregates; with time there is organization of these aggregates into paracrystalline deposits and well-ordered crystals. Crystals have only been observed outside cells to date suggesting that intracellular environments may inhibit ferritin crystallization or extracellular environments may promote crystal formation. Evolution and maintenance of lens transparency depends on suppressing expression of proteins, such as L-ferritin, that would otherwise form insoluble aggregates in lens. Further investigation into factors which normally suppress ferritin translation or stabilize ferritin aggregates is ongoing.
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