HUMAN LENS CONNEXIN GENES IN HEREDITARY CATARACT

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DESCRIPTION: Inherited cataract is a sight-threatening lens disease that usually presents as a congenital, autosomal dominant Mendelian trait showing high penetrance and considerable inter- and intra-familial clinical variation. The primary objective of this project is to determine whether mutations in the genes for connexin50 (Cx50) and connexin46 (CX46) underlie autosomal dominant forms of zonular pulverulent cataract that the PI has mapped to human chromosomes 1q and 13q, respectively. DNA cloning and sequencing techniques will be used to identify mutations and engineer constructs for functional expression studies on the wild-type and mutant forms of Cx50 and Cx46. The voltage-gating properties of wild-type and mutant forms Cx50 and Cx46 synthesized in Xenopus oocytes will be determined using a two microelectrode voltage clamp technique under defined pH conditions. The intercellular channel properties of wildtype and mutant forms Cx50 and Cx46 expressed in the connexin-deficient HeLa cell-line will be measured by fluorescent dye-transfer methods. Transgenic mouse techniques will be used to model the allelic interactions of wild-type and mutant forms of Cx50 and Cx46 that lead to cataract development in the living lens. Results from these studies will help to elucidate the pathogenetic mechanisms underlying a clinically important form of inherited cataract in humans and provide new insight into the role of connexins in human lens development. Ultimately, such data will contribute to the design of new preventative and therapeutic strategies for the clinical management of cataract.