Genetic and functional basis of connexins in disease

Abstract

Gap junctions are composed of connexin (Cx) proteins and permit the transfer of small molecules between cells. Six Cx proteins assemble to form a hemichannel, which can dock with an adjacent hemichannel on another cell to form a gap junction. Mutations in Cx genes are implicated in a range of diseases, however the mechanisms of how these mutations cause pathogenesis in vivo is largely unknown. Specific Cx genes were screened in patients with diseases that could be attributable to Cx mutations. This included patients with erythrokeratoderma variants erythrokeratoderma variabilis (EKV) and progressive symmetric erythrokeratoderma (PSEK), who were screened for GJB3 (Cx31) and GJB4 (Cx30.3) mutations. A novel heterozygous mutation p.L135V in Cx31 was found in a family with EKV. Novel sequence variants in GJB4 and LOR were also identified. Overexpression of EKV Cx31 mutants in vitro is associated with a cell death phenotype. Functional investigations performed indicate that hemichannel-mediated cell death is not the main mechanism of cell death associated with EKV Cx31 mutants and that ER stress may be important in disease pathogenesis. The genetic basis of erythrokeratoderma in patients who do not have disease-associated mutations in GJB3 or GJB4 was investigated. This led to the screening of candidate genes for disease in patients with erythrokeratoderma variants.