Hereditary and histologic characteristics of the CF1/b cac mouse cataract model

Abstract

A substrain of mice originating from the CF1 strain (an outbred colony) reared at Osaka Prefecture University (CF1/b cac mice) develops cataracts beginning at 14 d old. Affected mice were fully viable and fertile and had developed cataracts by 22 d of age. The incidence of cataracts did not differ between male and female mice. Histologically, 14-wk-old CF1/b cac mice showed vacuolated lens epithelial cells, swollen lens fibers, many pyknotic nuclei, and vacuolation of the lens cortex. To elucidate the mode of inheritance, we analyzed heterozygous mutants hybrids generated from CF1/b cac and wildtype BALB/c mice and the offspring of the backcrossed heterozygous mutants. None of the heterozygous mutants was affected, but the ratio of affected to unaffected mice was 1:3 among the offspring of the heterozygous mutants. The initial genomewide screen of 20 affected backcrossed offspring (CF1/b cac × [CF1/b cac × BALB/c]) indicated that the mutant gene resides on chromosome 16. For further mapping, we used affected progeny of CF1/b cac × (CF1/b cac × MSM/Ms) mice. We concluded that the cataracts in CF1/b cac mice are inherited through an autosomal recessive mutation and that the mutant gene is located on mouse chromosome 16 between D16Mit5 and D16Mit92 and between D16Mit92 and D16Mit201. The mapping of the mutant gene of the CF1/b cac mice to mouse chromosome 16 provides the positional information necessary to identify the candidate gene responsible for the CF1/b cac phenotype.

Figure 1.

Stereomicroscopic features of the lenses of CF1/b cac mice. (A) A 14-d-old CF1/b cac mouse. The lens has a focal opacity. (B) A 20-d-old CF1/b cac mouse. The opacity in the mouse is larger than that in the 14-d-old mouse.

Figure 2.

Eyes of adult (10-wk-old ddY (A) and 14-wk-old CF1/b cac mice [B through E]). (A) The eye is composed of several components (cornea, lens, retina, and so forth), with a normal lens. (B) The lens nucleus is dislocated posteriorly, and vacuoles (asterisks) are seen in the lens cortex. In the (C) anterior and (D) bow regions, vacuolated lens epithelial cells, piknotic nuclei (arrowheads), and swelling (arrows) of the lens fibers are seen. (E) The posterior region of the lens cortex shows swelling (arrows) of the lens fibers and liquefaction (asterisks) of the lens. C, cornea; LC, lens cortex; N, lens nucleus; R, retina; LE, lens epithelium.

Figure 3.

Lenses of neonatal CF1/b cac mice. (A) Lens of a 1-d-old CF1/b cac mouse is normal in appearance. (B) Transitional (anterior to bow) region of the lens of a 25-d-old CF1/b cac mouse demonstrates vacuoles (asterisks) in the lens cortex. In addition, vacuolated lens epithelial cells, piknotic nuclei (arrowheads), and swelling (arrows) of the lens fibers are present. (C) Anterior region of the lens of a 7-d-old CF1/b cac mouse. Swelling (arrows) of the lens fibers is seen. (D) Normal posterior region of the lens of a 7-d-old mouse. (E) Bow region of the lens of a 7-d-old mouse. Note the small vesicles beneath the lens epithelium. (F) Anterior region of the lens of a 14-d-old CF1/b cac mouse, with swelling (arrows) of the lens fibers. (G) Posterior region of the lens of a 14-d-old mouse shows swelling (arrows) of the lens fibers and pale lens fibers (arrow heads). (H) Bow region of the lens of a 14-d-old mouse, with small vesicles beneath vacuolated lens epithelium. (I) Anterior region of the lens of a 21-d-old CF1/b cac mouse. The lens fibers are swollen (arrows). (J) Posterior region of the lens of a 21-d-old mouse, in which swelling (arrows) of the lens fibers and liquefaction (asterisks) of the lens are seen. (K) Bow region of the lens of a 21-d-old mouse. Small vesicles are seen beneath the vacuolated lens epithelium.

Figure 4.

(A) Distribution of the haplotypes in a set of 256 affected offspring from the backcross (CF1/b cac × [CF1/b cac × MSM/Ms]). The typed loci are listed on the left. Columns denote specific chromosomes identified in affected backcrossed progeny. Values at the bottom of the figure are the number of progeny that inherited the indicated chromosomal haplotype from the F1 parent. Black squares represent the CF1/MSM allele; white squares represent the CF1/CF1 cac allele. (B) Genetic linkage map of chromosome 16. The map shows the location of the cataract gene of CF1/b cac mice (red arrows) and the Nct gene (black arrow). The typed loci are listed on the left.