The role of forkhead genes in eye development and disease

Extensive evidence has emerged for the important role of Forkhead Box (FOX) transcription factors in development through the description of mutations in model organisms and humans. Mutations in the forkhead gene FOXC1, on chromosome 6p25 cause a range of ocular developmental abnormalities with associated glaucoma. However FOXC1 mutations have not been found in all such pedigrees mapping to this region. Several similarly affected pedigrees were investigated by genotyping and fluorescent in-situ hybridisation, using markers and probes from 6p25, leading to the identification of segmental duplications and a segmental deletion that encompass FOXC1. These findings represent the first example of both segmental duplications and deletions co-segregating with a human developmental disorder that is attributable to altered transcription factor dosage. The data provides evidence for the pathogenicity of altered FOXC1 dosage, suggests that a common mechanism is responsible for rearrangements of 6p25 and forms the central part of this thesis. In order to recapitulate the human duplication phenotype efforts have been made to generate a transgenic murine model of the duplication. Further work investigated notable discrepancies between the phenotypes attributable to Foxc1 and FOXC1 mutations and those of a closely related forkhead gene Foxc2/FOXC2. The results have revealed a much wider role for FOXC1 and FOXC2 in ocular (and CNS) development and illustrate how meticulous scrutiny of differences between the known phenotypes caused by mutations in orthologous genes may represent a model for elucidating gene function