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First published online May 10, 2006
doi: 10.1242/10.1242/jcs.02940

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Knock-in of 3 connexin prevents severe cataracts caused by an 8 point mutation

¹ School of Optometry and Vision Science Program, University of California at Berkeley, Berkeley, CA, USA
² Program in Genetics, State University of New York, Stony Brook, NY, USA
³ The Jackson Laboratory, Bar Harbor, ME, USA
⁴ Department of Anatomy and Neurobiology, Morehouse School of Medicine, Atlanta, GA, USA
⁵ Department of Physiology and Biophysics, State University of New York, Stony Brook, NY, USA

^* Author for correspondence (e-mail: xgong{at}berkeley.edu)

Accepted 15 February 2006

A G22R point mutation in 8 connexin (Cx50) has been previously shown to cause a severe cataract by interacting with endogenous wild-type 3 connexin (Cx46) in mouse lenses. Here, we tested whether a knocked-in 3 connexin expressed on the locus of the endogenous 8 connexin could modulate the severe cataract caused by the 8-G22R mutation. We found that the 3(-/-) 8(G22R/-) mice developed severe cataracts with disrupted inner fibers and posterior rupture while the 3(-/-) 8(G22R/KI3) lens contained relatively normal inner fibers without lens posterior rupture. The 8-G22R mutant proteins produced typical punctate staining of gap junctions between fiber cells of 3(-/-) 8(G22R/KI3) lenses, but not in those of 3(-/-) 8(G22R/-) lenses. Thus, we hypothesize that the knocked-in 3 connexin subunits interact with the 8-G22R connexin subunits to form functional gap junction channels and rescue the lens phenotype. Using an electrical coupling assay consisting of paired Xenopus oocytes, we demonstrated that only co-expression of mutant 8-G22R and wild-type 3 connexin subunits forms functional gap junction channels with reduced conductance and altered voltage sensitivity compared with the channels formed by 3 connexin subunits alone. Thus, knocked-in 3 connexin and mutant 8-G22R connexin probably form heteromeric gap junction channels that influence lens homeostasis and lens transparency.

Key words: Gap junction, Connexin, Knock-in 3 (KI3), Cataract

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