A novelGJA3mutation associated with congenital nuclear pulverulent and posterior polar cataract in a chinese family

Abstract

Congenital cataract (CC) is the leading cause of visual disability in children. To date, mutations in many genes have been linked to CC. In a four-generation Chinese family with congenital nuclear pulverulent and posterior polar cataracts, we detected a heterozygous c.5G>A transition in the second exon of GJA3, resulting in the substitution of a highly conserved glycine with aspartic acid (p.G2D) at the N-terminus of the connexin46 (Cx46) protein. Wild type (wt) and mutant Cx46 plasmids were transfected into HeLa cells to examine the molecular basis of cataract formation. Unlike wt Cx46, Cx46G2D mutant formed gap junction plaques inefficiently, changed hemichannel permeability, and caused apoptosis. These results suggest that the glycine residue at the second position of the N-terminus is important for gap junction plaque formation and hemichannel function.

Expression and function of PDGF-α in columnar epithelial cells of age-related cataracts patients

“…Such cells express PDGFR and can be stimulated by PDGF. Previous reports on cells have confirmed that PDGF can promote cell proliferation and transformation to mesenchymal cells (Yao et al, 2011). Our clinical results confirmed that PDGF-α was overexpressed in the higher lesion.…”

Diseases associated with leaky hemichannels

“…Additionally, different Cx46 mutations have been associated with leaky HCs. For example, mutant Cx46G143R (located in the IL) leads to the appearance of Coppock cataracts ( Ren et al, 2013 ), and mutant Cx46G2D (located the NT) has been linked to formation of nuclear pulverulent and posterior polar cataracts ( Yao et al, 2011 ). Lower plasma membrane expression of these mutants was enough to promote cell death when expressed in HeLa cells ( Ren et al, 2013 ).…”

A Novel GJA8 Mutation (p.V44A) Causing Autosomal Dominant Congenital Cataract

“…Cx50G46V forms normal gap junctions, but it increased hemichannel activity [20] . Cx46G2N reduces hemichannel permeability, but it still forms gap junction plaques [11] . Moreover, Cx46G143R increases hemichannel function and causes apoptosis, even when the transfected cells are cultured at low density with minimal gap junctions [40] .…”

“…The cells were washed twice with Ca 2+ -free HBSS (Gibco). Dye uptake assays were performed by incubating each group of cells in Ca 2+ -free HBSS (Gibco) and in HBSS containing 1.2 mmol/L Ca 2+ or a specific hemichannel blocker, flufenamic acid (FFA, 300 µmol/L, Sigma, Saint Louis, MO, USA) [11] . All of the solutions were supplemented with 0.1% propidium iodide (PI, Sigma) or 0.1% 4′,6-diamidino-2-phenylindole (DAPI, Sigma).…”