Connexin46fs380 Causes Progressive Cataracts

Berthoud, Viviana M.; Minogue, Peter J.; Yu, Helena; Snabb, Joseph I.; Beyer, Eric C.

doi:10.1167/iovs.14-15012

Cited by 18 publications

(38 citation statements)

References 45 publications

(73 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have previously shown that Cx46fs380 lenses have decreased gap junctional coupling and develop progressive cataracts (3,28). In this study, we found that expression of Cx46fs380 altered fiber cell homeostasis, causing cell membrane depolarization, decreased activity of epithelial Na ϩ -K ϩ -ATPase, and increased center-to-surface gradients of hydro-static pressure and intracellular concentrations of sodium and calcium ions.…”

Section: Discussionmentioning

confidence: 58%

“…3 in the present study). These differences may reflect the reductions of Cx50 as well as Cx46 in Cx46fs380 lenses (3,28).…”

Section: Discussionmentioning

confidence: 99%

“…26). As Cx46fs380 mice grow older, fiber cell connexin levels continue decreasing (3,28), resulting in lower levels of gap junctional conductance. The significant increase in [Ca 2ϩ ] i finally exceeds limiting solubility values or overloads the buffering capacity of some lens cells, leading to the formation of Ca 2ϩ deposits.…”

Section: Discussionmentioning

confidence: 99%

“…Animals. Experiments were performed on Cx46fs380 mice, which were generated on a mixed 129/C57BL/6 genetic background (3).…”

Section: Methodsmentioning

confidence: 99%

“…This frame-shift mutant has an abnormal COOH terminus that contains a retention/retrieval signal, which prevents normal gap junction formation (29). These mice have significant reductions in the levels of Cx46 and Cx50 (likely due to their co-oligomerization with Cx46fs380 and subsequent degradation) and fiber cell gap junction intercellular conductance, and they develop progressive cataracts (3,28). These reductions would be expected to alter the contribution of gap junctions to the internal circulation of ions and fluid, giving rise to compensatory changes in other major components of the lens circulation.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

Gao

Minogue

Beyer

et al. 2018

American Journal of Physiology-Cell Physiology

Self Cite

View full text Add to dashboard Cite

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 Ca. 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 Ca. These data suggest that the lens internal circulation was disrupted by expression of Cx46fs380, leading to several consequences including accumulation of Ca to levels so high that precipitates formed. Similar Ca-containing precipitates may contribute to cataract formation due to other genetic or acquired etiologies.

show abstract

Section: Discussionmentioning

confidence: 58%

“…3 in the present study). These differences may reflect the reductions of Cx50 as well as Cx46 in Cx46fs380 lenses (3,28).…”

Section: Discussionmentioning

confidence: 99%