A junction of transparency. Focus on “Functional effects of Cx50 mutations associated with congenital cataracts”

Abstract

cataract, clouding of the optical lens of the eye, is an important health problem accounting for most of the blindness in the world. Eliminating cataract or even delaying cataract surgery (for those lucky enough to have access to surgery) would dramatically reduce health costs, but our ability to formulate pharmacological approaches to this end is hindered by our poor understanding of lens physiology. However, the situation is improving. A model that proposes an intrinsic lens fluid circulation (9) has proven an effective stimulus to innovative experiments in the lens and is receiving increasing experimental support. Knockout mouse studies have clarified the distinct roles played by connexin 50 (cx50, GJA8), connexin 46 (cx46), and connexin 43 (cx43) in lens development and maintenance of clarity. Knockout of either cx46 or cx50 (or both) produces a cataract, but only knockout of cx50 reduces lens size through a diminished rate of epithelial cell proliferation (7, 12, 13). Recent experiments have shown convincingly that connexins, especially cx46, provide a critical pathway for water flow driven by hydrostatic pressure (4). Like connexins, aquaporins play a critical role in lens transparency and naturally occurring mutants in many species including humans show that AQP0 is vital for lens transparency. At least three functions have been suggested for AQP0 in the lens: water channel (3, 10), adhesion molecule (5, 6, 14), and beaded filament anchor. Importantly, AQP0 interacts with connexin 50 (2, 8), the subject of the article by Rubinos et al. (11) in this issue of American Journal of Physiology-Cell Physiology. What is evident from the above is that even though we are making progress toward understanding lens physiology, there are clearly a myriad of details to be uncovered, and these will likely emerge from unexpected sources. The paper of Rubinos et al. provides a look at both the difficulties we face and the ways in which progress may be achieved. Rubinos et al. examine the functional properties of three cx50 mutants (as noted above a major player in maintaining lens clarity) that all produce congenital autosomal dominant cataracts in humans. The investigators focus on the single-channel properties and interactions with other connexins and identify three modes of disruption of the essential properties of connexin 50. One mutant cannot form conductive gap junctions on its own and disrupts the properties of wild-type junctions, hence the autosomal dominant phenotype. Another mutant cannot form channels on its own but can when mixed with either cx50 or cx46 wild-type connexins. So the dominant negative effect of this mutation is due to some other property of the mutant, perhaps defects in signaling, alteration of the permeability of the mixed (heteromeric) channels, or possibly altered interactions with AQP0. A third mutant forms channels with vastly different voltage gating properties from wild type and probably disrupts the conductance of wild-type channels leading to the autosomal dominant cataract phenotype. Taken together, Rubinos et al. characterize a zoo of point-mutation effects, all of which lead to autosomal dominant cataract, but in quite different fashion. Some of the mutations show dominant negative alteration of the channel properties of wild type, but one does not. Thus the results of this study both expand our understanding of the roles of cx50 in the lens as well as increase the perception of our ignorance concerning how cx50 interacts with other proteins in the lens. What are the immediate questions arising from this study to which we might wish answers? I have a few favorites. One avenue for future investigation is how the interactions between proteins contribute to lens transparency and how disruption of interactions spoils transparency. Another avenue is determining the role of genetic background on the penetrance of the mutations that Rubinos and colleagues have investigated. Related to this point, a classic study (1) revealed the importance of genetic background in either facilitating or preventing cataracts in the presence of a connexin mutation. In other words, the study of Rubinos et al. both increases our optimism that systematic study of lens physiology will eventually lead to a useful understanding of how to eliminate or delay cataract as well as warns us that the story is far from complete.