Mapping of A gene responsible for cataract formation and its modifier in the UPL rat.
OBJECTIVE
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.
D000375:Aging / Q000502:physiology; D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D002386:Cataract / Q000235:genetics*; D002874:Chromosome Mapping; D017630:Connexins; D005136:Eye Proteins / Q000235:genetics*; D005838:Genotype; D007178:Inbreeding; D008126:Lod Score; D008969:Molecular Sequence Data; D010641:Phenotype; D019655:Quantitative Trait, Heritable; D051381:Rats; D011922:Rats, Mutant Strains / Q000235:genetics; D000099264:Connexin 50
D017630:Connexins; D005136:Eye Proteins; D000099264:Connexin 50