Abstract
Abstract: :
Purpose:Hereditary hyperferritinemia cataract syndrome (HHCS) is an important example of disease due to protein deposition. The first type of catarct defined in HHCS results from aggregation and crystallization of L–ferritin protein. This affects almost all HHCS patients and appears as punctate, often radially distributed, opacities that are more common in the lens cortex than nucleus. By contrast, only a subset of HHCS subjects exhibit multipolar cataracts that appears as grape–like clusters of whitish vacuoles. Investigation of the molecular etiology of a distinct anterior polar cataract (APC) in HHCS was undertaken. Methods:Cataract morphology was obtained by slit lamp and Scheimpflug photography of multiple members of an HHCS kindred (IOVS 40:S899,B489). A transgenic mouse model was developed employing the L–ferritin promoter and gene modified by an HHCS mutation. Ferritin was detected by immuno histochemistry and fluorescence. Confocal differential interference contrast microscopy defined optically active ferritin arrays/crystals. Electron microscopy was used to define the ultrastructure of APCs obtained by capsulorhexis. Results:In Tg mice, ferritin accumulated within anterior lens epithlelial cells (LECs) as both inclusion bodies and paracrystalline arrays. Striking crystalline and non–crystalline ferritin deposits accrue at the apical epithelium only in the anterior lens. Rare,ferritin aggregates were surrounded by 50–70 micron wide cystic cavities at the LEC–cortex interface consistent with anterior subcapsular cataract. In human capsulorhexis specimens, significant overexpression of L–ferritin was evident in LECs and capsule. Anterior LECs exhibited membrane bound vacuoles and paracrystalline arrays consistent with dense ferritin aggregates. Large APCs, rich in collagen and ferritin, were found to extend inward from the capsule replacing the LECs. Conclusions:Together these results suggest a sequence of events which may culminate in APC of the HHCS lens in mice and humans: accumulation, aggregation and deposition of L–ferritin outside LECs with associated fibrosis. Ferritin deposition outside anterior LECs in HHCS is one of the first molecular risk factors identified for APC. HHCS illustrates distinct types of cataract resulting from ferritin deposition that differ in the degree of order in ferritin deposits from unordered deposit through paracrystalline arrays to frank crystals. Support: NIH EY00419
Keywords: cataract • clinical (human) or epidemiologic studies: natural history • pathobiology