Connexin Mutants Compromise the Lens Circulation and Cause Cataracts through Biomineralization.

Viviana M Berthoud,Oscar Jara,Eric C Beyer,Junyuan Gao,Peter J Minogue,Richard T Mathias

doi:10.3390/ijms21165822

Viviana M Berthoud, Oscar Jara + Show 4 more

Open Access

https://doi.org/10.3390/ijms21165822

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Abstract

Gap junction-mediated intercellular communication facilitates the circulation of ions, small molecules, and metabolites in the avascular eye lens. Mutants of the lens fiber cell gap junction proteins, connexin46 (Cx46) and connexin50 (Cx50), cause cataracts in people and in mice. Studies in mouse models have begun to elucidate the mechanisms by which these mutants lead to cataracts. The expression of the dominant mutants causes severe decreases in connexin levels, reducing the gap junctional communication between lens fiber cells and compromising the lens circulation. The impairment of the lens circulation results in several changes, including the accumulation of Ca2+ in central lens regions, leading to the formation of precipitates that stain with Alizarin red. The cataract morphology and the distribution of Alizarin red-stained material are similar, suggesting that the cataracts result from biomineralization within the organ. In this review, we suggest that this may be a general process for the formation of cataracts of different etiologies.

Highlights

Intercellular communication mediated by gap junctions is critical to the function of many organs
Studies of the connexins expressed in the eye lens have provided unique insights into the mechanisms by which connexin mutants and loss of intercellular communication lead to disease
Transgenic mice with lens over-expression of a mutant ubiquitin (K6W-Ub) that is conjugation competent but proteolytically incompetent have decreased gap junctional coupling between fiber cells in the core of the lens, likely because these mice have lower levels of Cx46, as detected by immunoblotting [22]. These results suggest that any gene mutation/deletion or insult that leads to a drastic decrease in the abundance and/or function of connexins in lens fiber gap junctions may reduce coupling between fiber cells

Summary

Introduction

Intercellular communication mediated by gap junctions is critical to the function of many organs. Gap junctions are plasma membrane specializations containing intercellular channels that allow the passage of cytoplasmic ions and small molecules (up to ~1 kDa) directly from cell to cell. They are formed by the coaxial alignment of two hemichannels; one is contributed by each of the closely apposed cells. Mutations of the genes encoding the connexins have been linked to a wide spectrum of diseases. The genetic disruption of the connexin-encoding genes can cause additional pathologies. Studies of the connexins expressed in the eye lens have provided unique insights into the mechanisms by which connexin mutants and loss of intercellular communication lead to disease. We summarize the findings of these studies and emphasize our recent observations

The Lens and Its Specialized Cells

Lens Disease and Connexins

Calcium Ions in the Normal and Cataractous Lens

Findings

Potential Generality of the Biomineralization Model for Cataract Formation