Abstract
Autosomal dominant congenital cataract (ADCC), the most common hereditary disease, is a major cause of eye disease in children. Due to its high genetic and clinical heterogeneity, the identification of ADCC-associated gene mutations is essential for the development of molecular therapies. In this study, we examined a four-generation Chinese pedigree with ADCC and identified putative mutations in ADCC candidate genes via next-generation sequencing (NGS) followed by Sanger sequencing. A novel missense mutation in GJA8 (c.T217C) in ADCC patients causes a serine-to-proline substitution at residue 73 of connexin 50 (Cx50); no mutation was found in unaffected family members and unrelated healthy individuals. Functional analysis revealed that this missense mutation disrupts protein function in human lens epithelial cells (HLEpiCs), which fails to form calcium-sensitive hemichannels. Furthermore, mutant Cx50 leads to decreased ROS scavenging by inhibiting G6PD expression and thus induces cell apoptosis via aberrant activation of the unfolded protein response (UPR). In conclusion, we report a novel GJA8 heterozygous mutation in a Chinese family with a vital role in ADCC, broadening the genetic spectrum of this disease.
Highlights
Autosomal dominant congenital cataract (ADCC), the most common hereditary disease, is a major cause of eye disease in children
Mutation analyses of six potential candidate genes associated with congenital cataracts, CRYGC, CRYGD, CRYGS, GJA8, GJA3 and CRYAA, revealed three mutations that generate premature stop codons, thereby truncating the protein, in CRYGD to be associated with congenital cataracts[9]
We clinically examined a four-generation Chinese family affected by ADCC with congenital perinuclear cataracts and identified a novel heterozygous missense mutation in GJA8 via next-generation sequencing, which we verified by Sanger sequencing
Summary
Autosomal dominant congenital cataract (ADCC), the most common hereditary disease, is a major cause of eye disease in children. We clinically examined a four-generation Chinese family affected by ADCC with congenital perinuclear cataracts and identified a novel heterozygous missense mutation in GJA8 via next-generation sequencing, which we verified by Sanger sequencing. We performed cellular experiments to dissect the pathogenic mechanism of this missense mutation and found that loss of hemichannel function and UPR activation might disrupt lens homeostasis and cause cataract formation. These findings extend our understanding of the molecular mechanism of ADCC and expand the mutational spectrum of Cx50 in Chinese ADCC patients
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