The study of inherited visual diseases provides a means by which both normal and aberrant visual processes might be understood. In addition to directly elucidating the pathophysiology of the inherited disease under study, these studies can provide insights into the structure- function relationships of the molecular components of the visual system and their normal physiology. This laboratory is using a number of approaches to study inherited visual diseases affecting the lens and retina. Lens crystallins comprise over 90% of the soluble protein of the lens and are heavily modified in most cataracts. The effects which specific modifications of beta- and gamma-crystallin structure produce on crystallin functions, such as stability and formation of macromolecular aggregates, are being studied in tissue culture cells transformed with normal and modified Beta A3/A1-crystallin genes. Regions of the beta- crystallin molecule of special interest include the amino terminal arm and the Greek key motifs of the core domains. The effects which these modifications have on lens transparency also being studied in a transgenic mouse system in which a modified beta-A3/A1 gene is driven by an alphaA-crystallin promoter. A second approach to understanding inherited visual diseases uses principles of positional cloning to identify genes important in human inherited diseases. Human diseases currently undergoing linkage analysis, gene isolation, or characterization of mutations include Usher syndrome, myotonic dystrophy, Duchenne muscular dystrophy, Long QT syndrome, cataracts, and a variety of X-linked syndromes. We currently are collecting families with autosomal recessive retinitis pigmentosa in preparation for study of this important group of diseases.
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