title: Cataract-causing mutation of human connexin 46 impairs gap junction, but increases hemichannel function and cell death.
abstract: 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.
authors.affiliation: First Hospital of Lanzhou University, Lanzhou, China ; Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas, United States of America.
authors.forename: Qian
authors.initials: Q
authors.lastname: Ren
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Riquelme
authors.forename: Ji
authors.initials: J
authors.lastname: Xu
authors.forename: Xiang
authors.initials: X
authors.lastname: Yan
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Nicholson
authors.forename: Sumin
authors.initials: S
authors.lastname: Gu
authors.forename: Jean X
authors.initials: JX
authors.lastname: Jiang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D002386:Cataract / Q000235:genetics*; D017630:Connexins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers; D017629:Gap Junctions / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid
chemical_list: D017630:Connexins; D017931:DNA Primers; C082917:GJA3 protein, human
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