First Hospital of Lanzhou University, Lanzhou, China ; Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas, United States of America.
PLoS One. 2013 Sep 3;8(9):e74732. doi: 10.1371/journal.pone.0074732. eCollection 2013.
Connexin channels play a critical role in maintaining metabolic homeostasis and transparency of the lens. Mutations in connexin genes are linked to congenital cataracts in humans. The G143R missense mutation on connexin (Cx) 46 was recently reported to be associated with congenital Coppock cataracts. Here, we showed that the G143R mutation decreased Cx46 gap junctional coupling in a dominant negative manner; however, it significantly increased gap junctional plaques. The G143R mutant also increased hemichannel activity, inversely correlated with the level of Cx46 protein on the cell surface. The interaction between cytoplasmic loop domain and C-terminus has been shown to be involved in gating of connexin channels. Interestingly, the G143R mutation enhanced the interaction between intracellular loop and Cx46. Furthermore, this mutation decreased cell viability and the resistance of the cells to oxidative stress, primarily due to the increased hemichannel function. Together, these results suggest that mutation of this highly conserved residue on the cytoplasmic loop domain of Cx46 enhances its interaction with the C-terminus, resulting in a reduction of gap junction channel function, but increased hemichannel function. This combination leads to the development of human congenital cataracts.
缝隙连接通道在维持代谢平衡和晶状体透明性方面起着关键作用。连接蛋白基因突变与人类先天性白内障有关。最近有报道称，连接蛋白（Cx）46 的 G143R 错义突变与先天性 Coppock 白内障有关。在这里，我们表明 G143R 突变以显性负性方式降低了 Cx46 缝隙连接偶联；然而，它显著增加了缝隙连接斑块。G143R 突变体还增加了半通道活性，与细胞表面 Cx46 蛋白的水平呈负相关。细胞质环域和 C 末端之间的相互作用已被证明参与连接蛋白通道的门控。有趣的是，G143R 突变增强了细胞内环和 Cx46 之间的相互作用。此外，这种突变降低了细胞活力和细胞对氧化应激的抵抗力，主要是由于半通道功能的增加。总之，这些结果表明 Cx46 细胞质环域上这个高度保守残基的突变增强了它与 C 末端的相互作用，导致缝隙连接通道功能降低，但半通道功能增加。这种组合导致了人类先天性白内障的发生。
