title: Cataracts and microphthalmia caused by a Gja8 mutation in extracellular loop 2.
abstract: The mouse semi-dominant Nm2249 mutation displays variable cataracts in heterozygous mice and smaller lenses with severe cataracts in homozygous mice. This mutation is caused by a Gja8(R205G) point mutation in the second extracellular loop of the Cx50 (or α8 connexin) protein. Immunohistological data reveal that Cx50-R205G mutant proteins and endogenous wild-type Cx46 (or α3 connexin) proteins form diffuse tiny spots rather than typical punctate signals of normal gap junctions in the lens. The level of phosphorylated Cx46 proteins is decreased in Gja8(R205G/R205G) mutant lenses. Genetic analysis reveals that the Cx50-R205G mutation needs the presence of wild-type Cx46 to disrupt lens peripheral fibers and epithelial cells. Electrophysiological data in Xenopus oocytes reveal that Cx50-R205G mutant proteins block channel function of gap junctions composed of wild-type Cx50, but only affect the gating of wild-type Cx46 channels. Both genetic and electrophysiological results suggest that Cx50-R205G mutant proteins alone are unable to form functional channels. These findings imply that the Gja8(R205G) mutation differentially impairs the functions of Cx50 and Cx46 to cause cataracts, small lenses and microphthalmia. The Gja8(R205G) mutation occurs at the same conserved residue as the human GJA8(R198W) mutation. This work provides molecular insights to understand the cataract and microphthalmia/microcornea phenotype caused by Gja8 mutations in mice and humans.
authors.affiliation: School of Optometry and Vision Science Program, University of California, Berkeley, California, United States of America.
authors.forename: Chun-Hong
authors.initials: CH
authors.lastname: Xia
authors.forename: Bo
authors.initials: B
authors.lastname: Chang
authors.forename: Adam M
authors.initials: AM
authors.lastname: Derosa
authors.forename: Catherine
authors.initials: C
authors.lastname: Cheng
authors.forename: Thomas W
authors.initials: TW
authors.lastname: White
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Gong
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002386:Cataract / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048430:Cell Shape; D002478:Cells, Cultured; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D006801:Humans; D015640:Ion Channel Gating; D007908:Lens, Crystalline / Q000473:pathology; D008564:Membrane Potentials; D051379:Mice; D008822:Mice, Transgenic; D008850:Microphthalmos / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA; D014617:Vacuoles / Q000378:metabolism; D014982:Xenopus laevis; D000099264:Connexin 50
chemical_list: D017630:Connexins; D005136:Eye Proteins; D000099264:Connexin 50; C082917:GJA3 protein, human