The cataract-inducing S50P mutation in Cx50 dominantly alters the channel gating of wild-type lens connexins.

Abstract:

:Mutations within connexin50 (Cx50) have been linked to various cataract phenotypes. To determine the mechanism behind cataract formation we used the paired Xenopus oocyte system in conjunction with transfected HeLa cells and genetically engineered mouse models to examine the functional characteristics of gap junctions in which a cataract-causing mutant of Cx50 (hereafter referred to as Cx50-S50P) is expressed. Channels comprising Cx50-S50P subunits alone failed to induce electrical coupling. However, the mixed expression of Cx50-S50P and wild-type subunits of either Cx50 or Cx46 - to create heteromeric gap junctions - resulted in functional intercellular channels with altered voltage-gating properties compared with homotypic wild-type channels. Additionally, immunofluorescence microscopy showed that channels of Cx50-S50P subunits alone failed to localize to the plasma membrane - unlike channels composed of Cx46 subunits, which concentrated at cell-cell appositions. Cx50-S50P colocalized with wild-type Cx46 in both transfected HeLa cells in vitro and mouse lens sections in vivo. Taken together, these data define the electrophysiological properties and intracellular targeting of gap junctions formed by the heteromeric combination of Cx50 or Cx46 and Cx50-S50P mutant proteins. Additionally, mixed channels displayed significantly altered gating properties, a phenomenon that may contribute to the cataract that is associated with this mutation.

journal_name

J Cell Sci

journal_title

Journal of cell science

authors

DeRosa AM,Xia CH,Gong X,White TW

doi

10.1242/jcs.012237

subject

Has Abstract

pub_date

2007-12-01 00:00:00

pages

4107-16

issue

Pt 23

eissn

0021-9533

issn

1477-9137

pii

jcs.012237

journal_volume

120

pub_type

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