The FOXC1 gene belongs to the forkhead box, or FOX, family of transcription factors, which comprises at least 43 members that are key regulators of embryogenesis, cell migration, and cell differentiation. These proteins are characterized by a conserved 110 amino acid DNA-binding domain, known as a forkhead domain (FHD). FOXC1 is expressed in the cornea, eye, heart, kidney, liver, lung, and muscles, where it plays a major role in embryonic and ocular development as a transcriptional factor and transcription regulator. Changes in the expression pattern of FOXC1 may cause changes in the expression patterns of hundreds genes.
The FOXC1 gene consists of one coding exon that spans approximately 3.45 kb in the genomic DNA. It encodes a transcription factor of 553 amino acids. Mutations in the FOXC1 gene have been identified as the underlying cause in a variety of anterior segment disorders, including primary congenital glaucoma, Axenfeld-Rieger syndrome type 3, Peters anomaly, and anterior segment mesenchymal dysgenesis. These mutations comprise frameshift and nonsense as well as missense mutations in the forkhead domain. In addition, interstitial duplications of the FOXC1 gene can lead to anterior segment dysgenesis and glaucoma.
Khan et al. (2008) performed FOXC1 mutational screening on an infant and her consanguineous parents. Both the infant and her mother were suffering from congenital glaucoma and aniridia. A heterozygous T>A point mutation was identified in the infant and her mother, but not the father, resulting in an amino acid substitution at a highly conserved methionine with lysine at position 161 (p.M161K). This mutation was not found in 100 Saudi controls. In a subsequent study to determine the genetic and genomic alterations underlying classic aniridia in Saudi Arabia, Khan et al. (2011) conducted a prospective study of consecutive patients referred to a pediatric ophthalmologist (2005-2009). All 12 probands (4 months-25 years of age; four boys and eight girls) were products of consanguineous unions except for three, one of which was endogamous. Heterozygous PAX6 mutations (including two novel mutations) were detectable in all but two cases, both of which were sporadic. In one of these two cases, the phenotype segregated with homozygosity for a previously-reported pathogenic missense FOXC1 variant (p.P297S) when homozygosity for chromosome 11q24.2 deletion (chr11:125,001,547-125,215,177 [rs114259885; rs112291840]) was also present. In the other, no genetic or genomic abnormalities were found. In year 2013, Khan et al. documented an unusual pattern of acquired peripheral circumferential iris degeneration in two unrelated children with otherwise-controlled congenital glaucoma. In one family, genetic testing revealed a novel heterozygous FOXC1 deletion (p.Tyr81_Pro95del).