title: A Gja8 (Cx50) point mutation causes an alteration of alpha 3 connexin (Cx46) in semi-dominant cataracts of Lop10 mice.
abstract: Mutations of connexin alpha 8 (GJA8 or Cx50) and connexin alpha 3 (GJA3 or Cx46) in humans have been reported to cause cataracts with semi-dominant inheritance patterns. Targeted null mutations in Gja8 and Gja3 in mice cause cataracts with recessive inheritance. The molecular bases for these differences in inheritance patterns and the mechanism for cataractogenesis in these mutants are poorly understood. We recently mapped an autosomal semi-dominant cataract [lens opacity 10 (Lop10)] mutation to mouse chromosome 3 and identified a missense mutation (G-->C) in the Gja8 gene, which causes glycine at codon 22 to be replaced with arginine (G22R). Moreover, we demonstrated that the alpha 8 G22R isoform is a loss-of-function mutant for alpha 8, as well as a dominant mutation for reducing the phosphorylated forms of alpha 3 connexin in vivo. To test the hypothesis that the alteration of endogenous alpha 3 connexin in Lop10 mice led to a unique lens phenotype, we generated double mutant offspring between Lop10 and the Gja3(tm1) (alpha 3(-/-)) mice. The double homozygous mutant mice (Lop10/Lop10 alpha 3(-/-)) showed relatively normal lens cortical fibers compared to the Lop10 mice. A functional impairment of endogenous alpha 3 connexin is therefore partly responsible for cellular phenotypes in the Lop10 mice. This study has provided some novel molecular insights into mouse and human cataractogenesis caused by alpha 8 and alpha 3 mutations. These mouse models will be useful for investigating the mechanistic relationship between gap junction impairment and cataract formation.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Chang
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Norman L
authors.initials: NL
authors.lastname: Hawes
authors.forename: Ryan
authors.initials: R
authors.lastname: Ojakian
authors.forename: Muriel T
authors.initials: MT
authors.lastname: Davisson
authors.forename: Woo-Kuen
authors.initials: WK
authors.lastname: Lo
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Gong
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001120:Arginine / Q000378:metabolism; D001483:Base Sequence; D002386:Cataract / Q000235:genetics* / Q000473:pathology; D002874:Chromosome Mapping; D003062:Codon; D017630:Connexins / Q000235:genetics*; D003433:Crosses, Genetic; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D005819:Genetic Markers; D005838:Genotype; D007908:Lens, Crystalline / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008850:Microphthalmos / Q000235:genetics / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics*; D017422:Sequence Analysis, DNA; D000099264:Connexin 50
chemical_list: D001120:Arginine; D003062:Codon; D017630:Connexins; D005136:Eye Proteins; D005819:Genetic Markers; D000099264:Connexin 50; C082917:GJA3 protein, human