FOXC1 and FOXL2 and the Axenfeld–Rieger Malformations and the Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome

Abstract

Abstract The complex process of embryogenesis proceeds through molecular signaling and regulation by developmentally important transcription factors. Of the regulatory molecules known, members of the evergrowing forkhead family of transcription factors are known to play key roles in the development of a wide range of organisms (Kaufmann and Knochel, 1996). Forkhead transcription factors are characterized by the presence of a conserved, 110-amino acid, DNA-binding domain; the forkhead domain (FHD). This DNA-binding motif is a variant of the helix–turn–helix motif, consisting of one minor and three major α-helices, two β-sheets, and two large loops that form “wing-like” structures. Consequently, FHDs are often referred to as winged-helix domains. Increasingly, winged-helix or FOX (Forkhead Box) genes have been shown to be involved in human heritable disorders. FOXC1 and FOXL2 are two of four FOX genes known to be involved with diseases possessing an ocular phenotype. FOXC1 mutations underlie ocular anterior segment dysgenesis with an increased risk of glaucoma and systemic defects, while FOXL2 mutations cause blepharophimosis ptosis and epicanthus inversus syndrome (BPES) (MIM 110100), an autosomal dominant disorder affecting the eyelids and tissues surrounding the eye. In this chapter, we discuss the involvement of FOXC1 and FOXL2 in development as well as describe the pathology when alterations to these genes are present.