Abstract
Purpose: :
A large number of human genetic diseases are caused by missense mutations in the genes. However, the targeted knockout of the respective gene in mice sometimes leads to early lethality, thus precluding a detail molecular understanding of the disease. To establish relevant viable mouse models of congenital ocular diseases we screened a large population of ENU mutagenized mice and identified a novel mutant with apparent cornea abnormalities.
Methods: :
ENU mutagenized C57/Bl6 mouse colony was phenotypically screened with a slit lamp to find mutants with abnormal anterior chamber development. The mutant mouse was bred to three different strain backgrounds to test for heritability, and to establish mapping families for linkage analyses. Genome-wide linkage analyses with >500 SNPs were performed to map the mutant to a small genetic interval. Candidate gene sequencing and reconfirmation of the mutant allele in multiple affected mice were performed to identify and establish the causal mutation. Histological analysis of the cornea was performed to assess developmental changes.
Results: :
The screen identified a recessive mutant. The mutant mouse exhibited a range of ocular phenotypes including open eyelids at the time of birth, microphthalmia, and corneal opacity. The mutant mice have no other significant morphological or reproductive abnormality. The mutation is recessive in nature and exhibits background dependent severity in phenotype. Position based cloning revealed a missense mutation in the FoxC1 gene. The mutation maps to the DNA binding region where several mutations in the human FoxC1 genes have been associated with Axenfeld Reiger Syndrome.
Conclusions: :
The mutant FoxC1 allele offers a mouse model to understand the molecular function of FoxC1 in ocular development. Ocular phenotypes and molecular characterization of the mutant protein will be discussed.
Keywords: cornea: basic science • mutations • transcription factors