Disruption of the lens circulation causes calcium accumulation and precipitates in connexin mutant mice

Abstract

The lens is an avascular organ whose function and survival depend on an internal circulation system. Cx46fs380 mice model a human autosomal dominant cataract caused by a mutant lens connexin. In these mice, fiber cell connexin levels and gap junction coupling are severely decreased. The present studies were conducted to examine components of the lens circulation system that might be altered and contribute to the pathogenesis of cataracts. Lenses from wild-type mice and Cx46fs380 heterozygotes and homozygotes were studied at 2 months of age. Cx46fs380-expressing lens fiber cells were depolarized. Cx46fs380 lenses had increased intracellular hydrostatic pressure and concentrations of Na⁺ and Ca²⁺. The activity of epithelial Na⁺-K⁺-ATPase was decreased in Cx46fs380 lenses. All of these changes were more severe in homozygous than in heterozygous Cx46fs380 lenses. Cx46fs380 cataracts were stained by Alizarin red, a dye used to detect insoluble Ca²⁺. These data suggest that the lens internal circulation was disrupted by expression of Cx46fs380, leading to several consequences including accumulation of Ca²⁺ to levels so high that precipitates formed. Similar Ca²⁺-containing precipitates may contribute to cataract formation due to other genetic or acquired etiologies.

Keywords: calcium; cataract; gap junction; lens; mutant connexin46.