HUMAN MULTIDRUG-RESISTANCE 3-P-GLYCOPROTEIN EXPRESSION IN TRANSGENIC MICE INDUCES LENS MEMBRANE-ALTERATIONS LEADING TO CATARACT

We have generated mice transgenic for a human multidrug resistance (MD R)3 mini-gene driven by a hamster vimentin promoter. The MDR3 gene enc odes a P-Glycoprotein that resembles the mouse multidrug resistance 2 P-Glycoprotein shown to be involved in the translocation of the phosph olipid phosphatidylcholine through the hepatocyte canalicular membrane (Smit et al., 1993, Cell. 75:451-462). The vimentin promoter drives e xpression of the MDR3 transgene in mesenchymal tissues and in the eye lens. We show here that the presence of human multidrug resistance 3 P -Glycoprotein in the lens results in a severe lenticular pathology. Le ns structural abnormalities initiate at a late embryonic stage and inc rease during postnatal lens development. Differentiation of the primar y fibers is affected, and the terminal differentiation of the lens epi thelium into secondary fibers is also perturbed. The ultrastructural a lterations, particularly of the lens plasma membranes, resemble those identified in congenital mouse osmotic cataract.