title: Novel PITX2 gene mutations in patients with Axenfeld-Rieger syndrome.
abstract: OBJECTIVE
  Mutations in the bicoid-like transcription factor PITX2 gene often result in Axenfeld-Rieger syndrome (ARS), an autosomal-dominant inherited disorder. We report here the discovery and characterization of novel PITX2 deletions in a small kindred with ARS.
  
  
  METHODS
  Two familial patients (father and son) from a consanguineous family were examined in the present study. Patient DNA samples were screened for PITX2 mutations by DNA sequencing and for copy number variation by SYBR Green quantitative polymerase chain reaction (PCR) analysis.
  
  
  RESULTS
  We report a novel deletion involving the coding region of PITX2 in both patients. The minimum size of the deletion is 1 421 914 bp that spans one upstream regulatory element (CE4), PITX2 and a minimum of 13 neighbouring genes. The maximum size of the deletion is 3 789 983 bp. The proband (son) additionally possesses a novel 2-bp deletion in a non-coding exon of the remaining PITX2 allele predicted to alter correct splicing.
  
  
  CONCLUSIONS
  Our findings implicate a novel deletion of the PITX2 gene in the pathogenesis of ARS in the affected family. This ARS family presented with an atypical and extremely severe phenotype that resulted in four miscarriages and the death at 10 months of age of a sib of the proband. As the phenotypic manifestations in the proband are more severe than that of the father, we hypothesize that the deletion of the entire PITX2 allele plus a novel 2-bp deletion (observed in the proband) within the remaining PITX2 allele together contributed to the atypical ARS presentation in this family. This is the first study reporting on bi-allelic changes of PITX2 potentially contributing to a more severe ARS phenotype.
authors.affiliation: Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Morteza
authors.initials: M
authors.lastname: Seifi
authors.affiliation: Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Tim
authors.initials: T
authors.lastname: Footz
authors.affiliation: Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Sherry A M
authors.initials: SA
authors.lastname: Taylor
authors.affiliation: Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt.
authors.forename: Ghada M
authors.initials: GM
authors.lastname: Elhady
authors.affiliation: Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt.
authors.forename: Ebtesam M
authors.initials: EM
authors.lastname: Abdalla
authors.affiliation: Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada. mwalter@ualberta.ca.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Walter
mesh_terms: D000328:Adult; D000869:Anterior Eye Segment / Q000002:abnormalities*; D002675:Child, Preschool; D003241:Consanguinity; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005124:Eye Abnormalities / Q000235:genetics*; D015785:Eye Diseases, Hereditary; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D016366:Open Reading Frames / Q000235:genetics; D010375:Pedigree; D060888:Real-Time Polymerase Chain Reaction; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics*; D000097577:Homeobox Protein PITX2
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2
keywords: chromosome 4q25; compound heterozygote; deletion; glaucoma; transcription factor