title: Identification of dominant FOXE3 and PAX6 mutations in patients with congenital cataract and aniridia.
abstract: OBJECTIVE
  Aniridia and congenital cataract represent rare but severe developmental ocular conditions. We examined 33 probands from France for mutations in several transcription factors associated with these phenotypes, the forkhead box E3 (FOXE3), paired box gene 6 (PAX6), paired-like homeodomain transcription factor 2 (PITX2), and paired-like homeodomain transcription factor 3 (PITX3) genes.
  
  
  METHODS
  Out of 33 probands, 27 were affected with congenital cataract while the remaining six were affected with aniridia (with or without cataract). The coding regions of FOXE3, PAX6, PITX2, and PITX3 were examined by direct DNA sequencing of gene-specific PCR products.
  
  
  RESULTS
  A novel dominant mutation at the stop codon of FOXE3, c.959G>C (p.X320SerextX72), was identified in a patient with congenital cataract. Another novel FOXE3 sequence change, c.571-579dup (p.Tyr191_Pro193dup), was identified in a patient with aniridia, mild lens opacities, and some additional ocular defects; this patient was also found to carry a nonsense mutation in PAX6. PAX6 mutations were identified in two additional probands with aniridia and cataracts. None of the observed sequence alterations were found in normal controls. No mutations were identified in PITX2 or PITX3.
  
  
  CONCLUSIONS
  The p.X320SerextX72 mutation is only the fourth FOXE3 allele associated with a dominant phenotype since the majority of FOXE3 mutations appear to be recessive with no phenotype observed in heterozygous carriers. The encoded protein is predicted to contain a complete normal sequence followed by seventy-two erroneous amino acids; the position and effect of this mutation are similar to two of the previously reported dominant changes, suggesting a common mechanism for dominant alleles. The p.Tyr191_Pro193dup is predicted to result in an in-frame duplication of three amino acids; however, the contribution of this mutation to the phenotype is unclear since the affected patient also carries a nonsense mutation in PAX6 which acts upstream of FOXE3 in the molecular pathway. The identified PAX6 mutations correspond to the two most commonly observed mutant alleles and demonstrate phenotypes that are consistent with the previously reported spectrum.
authors.affiliation: Department of Pediatric Ophthalmology, St Victor University Hospital of Amiens, INSERM UMRS968, Vision Institute, Paris VI University, Amiens, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Brémond-Gignac
authors.forename: Pierre
authors.initials: P
authors.lastname: Bitoun
authors.forename: Linda M
authors.initials: LM
authors.lastname: Reis
authors.forename: Henri
authors.initials: H
authors.lastname: Copin
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.forename: Elena V
authors.initials: EV
authors.lastname: Semina
mesh_terms: D000595:Amino Acid Sequence; D015783:Aniridia / Q000150:complications* / Q000235:genetics*; D001483:Base Sequence; D002386:Cataract / Q000150:complications / Q000151:congenital* / Q000235:genetics; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics*; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics*; D005799:Genes, Dominant / Q000235:genetics*; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000737:chemistry / Q000235:genetics*; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: D005136:Eye Proteins; C404285:FOXE3 protein, human; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins
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