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 visual system. Lens crystallins comprise more than 90 percent of the soluble protein of the lens and are heavily modified in most cataracts. The effects that specific modifications of beta- and gamma-crystallin structure produce on crystallin functions, such as stability and formation of macromolecular aggregates, are being studied using SF9 cells transformed with baculovirus vector containing coding sequences for normal and modified beta A3/Al- and beta B2-crystallin genes. Regions of the beta-crystallin molecule of special interest include the amino and carboxy terminal arms, the connecting peptide, and the Greek key motifs of the core domains. In addition, the interactions of acidic and basic beta-crystallins are being studied. A second approach to understanding inherited visual diseases uses the 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, cataracts, x-linked retinoschesis, and x-linked familial exudative vitreoretinopathy. We are currently collecting families with autosomal recessive retinitis pigmentosa and Bietti syndrome in preparation for study of this important group of diseases. The effects of specific genetic alterations, including glutathione S-transferase M1 deletions on the visual process, are being studied. Finally, families with individuals affected by multifactorial diseases, such as progressive open-angle glaucoma and age-related cataracts, are being collected to study the genes affecting these complex diseases.
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