Purpose: We have discovered a spontaneous and severe mutation that leads to partial or complete disruption of the lens and cataract in the RIIIS/J inbred strain of mice. The purpose of this study was to determine the mode of inheritance, specificity, and range of phenotypes using histological, ophthalmic, quantitative electron microscopic, and microarray-based methods. We also have fine-mapped the mutation, ldis1 (lens disrupter 1), and have evaluated positional candidate genes.
Methods: Eyes from mutant RIIIS/J animals and from an F2 intercross between RIIIS/J and DBA/2J were examined and scored to map the ldis1 mutation. Axons in the optic nerve were counted. Messenger RNA from mutant eyes was hybridized to Affymetrix short oligomer microarrays and compared to five control strains. Expression differences were used to evaluate molecular sequellae of the mutation.
Results: Mice that are homozygous for ldis1 have small eyes. Lenses are without exception opaque, deformed, dislocated, fragmented, and small. In contrast, retinal architecture and ganglion cell numbers are within normal range. We have not detected any other ldis1-associated ocular or systemic abnormalities. ldis1 is recessive and maps to chromosome 8 at about 106.5 Mb between D8Mit242 and D8Mit199 with a peak LOD score near cadherin 1. The homologous human chromosomal interval is 16q22.1. The expression of several downstream crystallin transcripts are severely affected in the mutant, as are the expression levels of multiple members of the transforming growth factor superfamily and the glutathione S-transferases.
Conclusions: We have discovered and mapped a recessive mutation to mouse chromosome 8 between 105 and 109 Mb. Homozygous mutant mice have a selective and severe effect on lens integrity. On the basis of the phenotype and the locus position, several candidate genes have been identified.