A Gja8 (Cx50) point mutation causes an alteration of alpha3 connexin (Cx46) in semi-dominant cataracts of Lop10 mice.
Hum Mol Genet 2002 Mar; 11(5):507-13.
Mutations of connexin alpha8 (GJA8 or Cx50) and connexin alpha3 (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 (Gright arrowC) in the Gja8 gene, which causes glycine at codon 22 to be replaced with arginine (G22R). Moreover, we demonstrated that the alpha8 G22R isoform is a loss-of-function mutant for alpha8, as well as a dominant mutation for reducing the phosphorylated forms of alpha3 connexin in vivo. To test the hypothesis that the alteration of endogenous alpha3 connexin in Lop10 mice led to a unique lens phenotype, we generated double mutant offspring between Lop10 and the Gja3(tm1) (alpha3(--/--)) mice. The double homozygous mutant mice (Lop10/Lop10 alpha3(--/--)) showed relatively normal lens cortical fibers compared to the Lop10 mice. A functional impairment of endogenous alpha3 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 alpha8 and alpha3 mutations. These mouse models will be useful for investigating the mechanistic relationship between gap junction impairment and cataract formation.
Chang, B; Wang, X; Hawes, N L.; Ojakian, R; Davisson, M T.; Lo, W K.; and Gong, X, " A Gja8 (Cx50) point mutation causes an alteration of alpha3 connexin (Cx46) in semi-dominant cataracts of Lop10 mice." (2002). Faculty Research 2000 - 2009. 363.