Human Molecular Genetics, 2002, Vol. 11, No. 5 507-513
© 2002 Oxford University Press
A Gja8 (Cx50) point mutation causes an alteration of 
3 connexin (Cx46) in semi-dominant cataracts of Lop10 mice
The Jackson Laboratory, Bar Harbor, ME, USA, 1Department of Cell Biology, The Scripps Research Institute, IMM10, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA and 2Morehouse School of Medicine, Atlanta, GA, USA
Mutations of connexin 
8 (GJA8 or Cx50) and connexin 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 8 G22R isoform is a loss-of-function mutant for 8, as well as a dominant mutation for reducing the phosphorylated forms of 3 connexin in vivo. To test the hypothesis that the alteration of endogenous 3 connexin in Lop10 mice led to a unique lens phenotype, we generated double mutant offspring between Lop10 and the Gja3tm1 (3–/–) mice. The double homozygous mutant mice (Lop10/Lop10 3–/–) showed relatively normal lens cortical fibers compared to the Lop10 mice. A functional impairment of endogenous 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 8 and 3 mutations. These mouse models will be useful for investigating the mechanistic relationship between gap junction impairment and cataract formation.
+ To whom correspondence should be addressed. Tel: +1 858 784 8842; Fax: +1 858 784 9132; Email: gong@scripps.edu
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