A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye

Mutations in the forkhead transcription-factor gene (FOXC1), have been show n to cause defects of the anterior chamber of the eye that are associated w ith developmental forms of glaucoma. Discovery of these mutations was great ly facilitated by the cloning and characterization of the 6p25 breakpoint i n a patient with both congenital glaucoma and a balanced-translocation even t involving chromosomes 6 and 13. Here we describe the identification of no vel mutations in the FOXC1 gene in patients with anterior-chamber defects o f the eye. We have detected nine new mutations (eight of which are novel) i n the FOXC1 gene in patients with anterior-chamber eye defects. Of these mu tations, five frameshift mutations predict loss of the forkhead domain, as a result of premature termination of translation. Of particular interest is the fact that two families have a duplication of 6p25, involving the FOXC1 gene. These data suggest that both FOXC1 haploinsufficiency and increased gene dosage can cause anterior-chamber defects of the eye.