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Purpose: The Upjohn Pharmaceuticals Limited (UPL) rat is a unique model for cataracts, which are inherited as an autosomal semidominant trait and expressed as early-onset (E-type) cataracts in homozygotes and as late-onset (L-type) cataracts in heterozygotes. In this study, a gene and its modifier, which are responsible for formation of cataract, were mapped.
Methods: Fifty-five BN x (BN x UPL)F(1) backcross rats and 133 BN x UPL intercross rats were produced. The cataracts present in the rats at eye opening were diagnosed as E-type. Cataracts that developed after eye opening were diagnosed as L-type, and the ages when complete opacity in the lens was observed were used as a quantitative trait to map a gene that modifies the development of mature cataracts. Linkage analysis was performed using 64 arbitrarily primed-representational difference analysis (AP-RDA) markers and 74 microsatellite markers.
Results: A gene responsible for the formation of cataract was mapped to the vicinity of D2Rat134 on rat chromosome (chr) 2. A candidate gene, connexin 50 (Cx50/Gja8), had a C-to-T transition at codon 340 that is predicted to result in a nonconservative substitution of arginine by tryptophan. Recombination in the Cx50 genotype and formation of cataract was not observed. By quantitative trait loci analysis, a gene that modified the age of the development of mature cataract was mapped on rat chr 5.
Conclusions: A candidate gene for formation of cataracts in UPL rats was mapped to rat chr 2, and the Cx50 gene was a strong candidate. In addition, a potential modifier gene was mapped on chr 5. Future cloning of these genes will provide good targets for new therapies that can delay the progression of cataracts.
Research papers (academic journals)
