Axenfeld–Rieger Syndrome: Coexistence of Mutations in the FOXC1 and GJA1 Genes

Abstract

Abstract: : Purpose: Axenfeld–Rieger syndrome is an autosomal dominant disorder with phenotypic heterogeneity characterized by anterior segment dysgenesis, facial bone defects and periumbilical skin involution. Approximately 50% of the cases are associated with developmental glaucoma. PITX2 gene , on chromosome 4q25 and FOXC1 gene, on chromosome 6p25, have been implicated in the different phenotypes of the syndrome through mutational events. Recently, the gene associated with oculodentodigital dysplasia (ODDD) syndrome, that presents some similarities with ARS, was identified (connexin 43 – GJA1 gene). The ODDD syndrome is characterized by malformations that involve face, eyes, teeth and bones. The ocular abnormalities include microphthalmos and anterior segment dysgenesis that may lead to glaucoma as well. The purpose of this study was to evaluate FOXC1, PITX2 and GJA1 gene mutations in a Brazilian family with ARS Methods: A three generation family (10 individuals) affected by ARS was evaluated ophthalmologically and had their blood collected for DNA extraction purposes. All the coding region of these genes were evaluated through direct sequencing. Results: A new nonsense mutation (Trp152STOP) was identified in the forkhead domain of the FOXC1 gene segregating with the disease and a new mutation in the GJA1 gene (Ala253Val) was observed in two affected patients of the second generation. Patients who carried the GJA1 (Ala253Val) and FOXC1 (Trp152STOP) mutations developed a less severe glaucoma compared with family members presenting FOXC1 (Trp152STOP) mutation alone. No structural alterations were found in the PITX2 gene. Conclusions: New mutations were described in both FOXC1 and GJA1 genes in a family with ARS. A mutation in the GJA1 gene, for the first time evaluated in this syndrome, raises the possibility of its enrollment as a modifier gene.

Keywords: genetics • mutations • transcription factors