The Molecular and Biochemical Basis of Axenfeld-Rieger Syndrome

Abstract

Mutations in the PITX2 homeobox gene are associated with Axenfeld-Rieger syndrome (ARS) and provided the first link of this transcription factor to tooth, eye, heart, and pituitary development. We are investigating the molecular basis of developmental anomalies associated with human PITX2 mutations. PITX2 mutant proteins exhibit a variety of transcriptional defects including, instability, decreased DNA binding activity, DNA binding without transcriptional activation, phosphorylation defects, increased transcriptional and dominant negative activities. ARS is a haploinsufficiency disorder and because PITX2 proteins can dimerize the effects of the PITX2 mutations can cause heterogeneous developmental anomalies in these patients. FOXC1 is a member of the Forkhead Box transcription factor family that play key roles in development, including morphogenesis and cell fate specification. FOXC1 mutations are associated with ARS and Axenfeld-Rieger Anomaly (ARA) that result in a spectrum of glaucoma phenotypes in humans. Missence mutations in the FOXC1 forkhead domain result in impaired DNA binding and reduced transactivation of target genes. Pax6 is a paired-like homeobox gene and recently a mutation in this transcription factor has been linked to Rieger syndrome. This report will summarize the molecular/biochemical mechanism of these developmental transcription factors and how they correlate with the clinical manifestations of ARS and ARA.