A New Mouse Mutation Develops Nuclear Cataract in Heterozygote While Posteriorly Ruptured Lens in Homozygote

Abstract

Abstract: : Purpose: To identify mouse new cataract mutation from ENU–mutagenized mice and to characterize the lens phenotypes of BEML23 line Methods: Mutagenized mice were generated by a forward genetic approach using alkylating agent N–ethyl–N–nitrosourea (ENU) to induce random mutations in mouse genome. The phenotype of mouse eye and lens was evaluated by indirect ophthalmoscope. The cellular and biochemical changes were characterized by standard histology, immunohistochemistry, and biochemical methods. Results:Mouse BEML23 (L23) line is a dominant cataract mutation identified from a screen of ENU–mutagenized F1 mice by slit lamp examination. Heterozygous mice develop normal size eyeballs and lenses with nuclear cataracts while homozygous mice show microphthalmia and posteriorly ruptured lenses at the age of 3 weeks. Their lens phenotypes are similar to that of mouse Lop10 (connexin α8–G22R mutation) line. Western blotting and immunohistochemical staining verified no obvious changes of the properties of both connexin α3 (Cx46) and α8 (Cx50) in L23 lenses. DNA sequencing further verified no mutation in the coding region of α8 connexin. Conclusions: Mouse L23 line is a new and unique cataract model. Its lens phenotypes are dependent on the dosage of mutant alleles. Although L23 cataracts are similar to the cataracts caused by α8 connexin (Cx50) mutation, but α8 connexin gene is not L23 causative gene. Therefore, it is important to determine the mutated gene in L23 line, to study the molecular basis how this mutation leads to two different types of cataracts, and why its lens defects are similar to α8 connexin mutation. We are in the process to map the chromosome location of L23 mutation by a genome–wide linkage analysis and to perform a detailed morphological analysis.

Keywords: cataract • mutations • gene mapping