title: Structural assessment of PITX2, FOXC1, CYP1B1, and GJA1 genes in patients with Axenfeld-Rieger syndrome with developmental glaucoma.
abstract: OBJECTIVE
  Axenfeld-Rieger (AR) is an autosomal dominant disorder with phenotypic heterogeneity characterized by anterior segment dysgenesis, facial bone defects, and redundant periumbilical skin. The PITX2 gene, on chromosome 4q25, and the FOXC1 gene, on chromosome 6p25, have been implicated in the different phenotypes of the syndrome through mutational events. Recently, the CYP1B1 gene was found to be associated with Peters' anomaly, and the gene associated with oculodentodigital dysplasia syndrome, which presents some similarities with AR, was identified (connexin 43--GJA1 gene). The purpose of this study was to evaluate PITX2, FOXC1, CYP1B1, and GJA1 gene mutations in Brazilian families with AR.
  
  
  METHODS
  Eight unrelated patients affected by AR (all eight with glaucoma and three with systemic manifestations) and their families were ophthalmologically evaluated and their blood was collected for DNA extraction purposes. The coding regions of PITX2, FOXC1, CYP1B1, and GJA1 genes were completely evaluated through direct sequencing.
  
  
  RESULTS
  The frequency of mutations in the FOXC1, GJA1, PITX2, and CYP1B1 genes in this study were 25%, 12.5%, 0% and 0%, respectively. In the FOXC1 gene, two GGC triplet insertions (GGC375ins and GGC447ins) defined as a polymorphism, and two new mutations--a deletion (718 to 719delCT) and a nonsense mutation (Trp152STOP)--were identified. One polymorphism (Ala253Val) was identified in the GJA1 gene in the same family presenting the Trp152STOP mutation in the FOXC1 gene. In this family harboring both structural alterations, two patients who carried the GJA1 (Ala253Val) and FOXC1 (Trp152STOP) mutations developed less severe glaucoma compared with family members presenting the FOXC1 (Trp152STOP) mutation alone.
  
  
  CONCLUSIONS
  Two new structural alterations in the FOXC1 gene and a polymorphism in the GJA1 gene were first described in Brazilian patients with AR and developmental glaucoma. A polymorphism in the GJA1 gene (Ala253Val), for the first time identified in association with AR, raises the possibility of its participation as a modifier gene.
authors.affiliation: Department of Ophthalmology, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil. wenercella@ig.com.br
authors.forename: Wener
authors.initials: W
authors.lastname: Cella
authors.forename: José Paulo Cabral
authors.initials: JP
authors.lastname: de Vasconcellos
authors.forename: Mônica Barbosa
authors.initials: MB
authors.lastname: de Melo
authors.forename: Bianca
authors.initials: B
authors.lastname: Kneipp
authors.forename: Fernando Ferreira
authors.initials: FF
authors.lastname: Costa
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Longui
authors.forename: Vital Paulino
authors.initials: VP
authors.lastname: Costa
mesh_terms: D000293:Adolescent; D000328:Adult; D000869:Anterior Eye Segment / Q000002:abnormalities*; D001189:Aryl Hydrocarbon Hydroxylases; D002648:Child; D018031:Connexin 43 / Q000235:genetics*; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004252:DNA Mutational Analysis; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005901:Glaucoma / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*; D000097577:Homeobox Protein PITX2
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D018031:Connexin 43; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C112743:FOXC1 protein, human; C500216:GJA1 protein, human; C585496:CYP1B1 protein, human