title: Detailed ophthalmologic evaluation of 43 individuals with PAX6 mutations.
abstract: OBJECTIVE
  Heterozygous mutations of the PAX6 gene cause a variety of ocular malformations, the best known being aniridia (absence of the iris). Mutation analyses and detailed clinical evaluations were performed in 43 individuals with aniridia or closely related ocular anomalies, to investigate whether phenotype correlates with mutation type.
  
  
  METHODS
  Case notes and medical records were reviewed and patients were reexamined when necessary. Denaturing high-performance liquid chromatography (DHPLC) analysis and sequencing of the PAX6 coding region was performed in individuals whose mutation was unknown.
  
  
  RESULTS
  The most common PAX6 mutations identified were premature termination mutations, amino acid substitutions, and C-terminal extensions. Six novel mutations are reported. Mutations that inactivate one copy of the gene typically caused a severe phenotype including foveal hypoplasia, marked iris anomalies, and severe visual impairment. Missense mutations, all affecting invariant amino acids in the paired domain, caused milder phenotypes in this cohort, with a lower incidence of foveal hypoplasia and less severe visual loss. C-terminal extension mutations caused relatively severe anomalies and marked reduction in vision. Two C-terminal extension cases had a unilateral exudative retinopathy, resembling Coats' disease, which has not previously been reported in association with PAX6 mutation.
  
  
  CONCLUSIONS
  PAX6 mutations cause panocular malformations that vary considerably in pattern and severity. In our cohort, iris hypoplasia, nystagmus, and foveal hypoplasia were most common, with cataracts, corneal anomalies, and high refractive errors also frequently observed. In this cohort, loss-of-function and C-terminal extension mutations were found to cause more severe phenotypes than missense mutations.
authors.affiliation: Moorfields Eye Hospital, London, United Kingdom.
authors.forename: Melanie
authors.initials: M
authors.lastname: Hingorani
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Williamson
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.forename: Veronica
authors.initials: V
authors.lastname: van Heyningen
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D005124:Eye Abnormalities / Q000235:genetics* / Q000473:pathology; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics*; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins