Cataractogenesis, Connexin Mutants &Genetic Modifier(s)

Scripps Research Institute, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Two unique and important features of the mammalian lens in its function of transmitting and focusing light onto the retina are: 1.) a finely regulated cell-cell communication network associated with the standing circulation current for both the metabolic and electrical coupling of lens cells, and 2.) precisely organized cellular and molecular architectures to prevent the light from scattering. Molecular genetic studies have verified the essential role(s) of connexin genes in cataractogenesis in humans and in mice. However, neither the molecular mechanisms for the interaction and regulation between different connexin genes in the lens, nor the molecular basis for the cataractogenesis that is linked to these connexin gene mutants, is well understood. It is, moreover, completely unknown how other genetic components manifest the variable expression of cataracts associated with connexin mutants in humans and in mice. Based on the literature and on our preliminary studies of natural, spontaneous connexin mutant mice in comparison with their gene knockout mice, we hypothesize that some of the connexin mutants change the properties of the gap junction channels which they formed, subsequently altering the permeation of this essential, low-resistance cell-cell pathway that allows for the passage of small molecules directly diffused between the cytosols of attached lens cells. Secondly, we hypothesize that gap junctions are also utilized as one of the necessary adhesive structural components in the plasma membrane for maintaining lens cell surface architecture. The proposed work is designed to study the mechanisms for cell-cell communication and lens cell surface architecture, both of which are related to the function of the connexin genes, other related lens genes, and/or other genetic factor(s).