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Abstract

Abstract 

  1. Cells of the eye lens are derived from the surface ectoderm and consist of a single cell type which, as they differentiate into fiber cells, lose their protein synthetic capabilities. In addition to cytoskeletal and membrane components, lens cells contain large amounts of structural proteins called crystallins. Because proteins in the lens nucleus cannot be replaced, they must be stable in the face of oxidative and ultraviolet insults.

  2. Lens crystallins, which are structural proteins contributing to lens transparency, comprise more than 90 percent of the soluble protein. Lenses of most species contain α-, β-, and γ-crystallins, also called ubiquitous crystallins. α-Crystallins are heat-shock proteins also found in a variety of nonlens tissues. In addition to their refractive roles, the α-crystallins serve as molecular chaperones to prevent protein aggregation resulting from oxidative stress and thus protect the lens from cataract. The β- and γ-crystallins belong to a superfamily with the microbial stress proteins.

  3. In addition to the ubiquitous crystallins, there are also proteins called taxon-specific crystallins, which occur at a high concentration in the lens but are present only in selected species. Many of the taxon-specific crystallins function as enzymes in nonlens tissues, where they are expressed at low concentrations. These enzyme crystallins seem to have arisen by a process called gene sharing, in which a single gene may acquire more than one function in several tissues.

  4. One requirement for a protein to function as a crystallin is the ability for it to be expressed at high levels in the lens. Transcriptional regulation, which is accomplished through a complex combination of cis and trans regulatory elements, appears to be very important for the high expression of crystallins in the lens.

  5. Lens transparency also requires maintenance of a reduced state to minimize oxidative damage to crystallins and other proteins over their long lifetimes. To do this, the lens uses multiple mechanisms. The glutathione redox cycle is especially important. In addition, osmotic balance is critical for lens transparency, and the lens accomplishes this by a combination of active transport by the anterior cuboidal epithelia and an extensive array of communicating channels connecting lens fiber cells.

  6. Animal models for human cataracts have contributed a great deal to our knowledge of this disease. They show that mutations in genes encoding lens crystallins, including βB2-crystallin, γ-crystallins, and ζ-crystallin, and proteins necessary for cellular homeostasis, especially intercellular communication and membrane proteins, including MP26 and MP19, can lead to cataracts. In addition, mice in which homologous recombination has been used to inactivate a number of genes including αA-crystallin, osteonectin, connexin43, and connexin46, develop cataract.

  7. In humans, many genes appear to be able to cause cataracts. Linkage studies have implicated multiple loci in cataractogenesis, and mutations in candidate genes at linked loci, including αC-crystallin, αD-crystallin, βB2-crystallin, βA3-crystallin, αA-crystallin, phakinen, MIP, connexin46, and connexin50, have been associated with human cataracts. In addition, cataracts can occur as part of many inherited and chromosomal syndromes.

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