title: Novel anterior segment phenotypes resulting from forkhead gene alterations: evidence for cross-species conservation of function.
abstract: OBJECTIVE
  Mutations in murine and human versions of an ancestrally related gene usually result in similar phenotypes. However, interspecies differences exist, and in the case of two forkhead transcription factor genes (FOXC1 and FOXC2), these differences include corneal or anterior segment phenotypes, respectively. This study was undertaken to determine whether such discrepancies provide an opportunity for identifying novel human-murine ocular phenotypes.
  
  
  METHODS
  Four pedigrees with early-onset glaucoma phenotypes secondary to segmental chromosomal duplications or deletions encompassing FOXC1 and 18 individuals from 9 FOXC2 mutation pedigrees underwent detailed ocular phenotyping. Subsequently, mice with mutations in Foxc1 or a related forkhead gene, Foxe3, were assessed for features of the human phenotypes.
  
  
  RESULTS
  A significant increase in central corneal thickness was present in affected individuals from the segmental duplication pedigrees compared with their unaffected relatives (mean increase 13%, maximum 35%, P < 0.05). Alterations in corneal thickness were present in mice heterozygous and homozygous for Foxe3 mutations but neither in Foxc1 heterozygotes nor the small human segmental deletion pedigree. Mutations in FOXC2 resulted in ocular anterior segment anomalies. These were more severe and prevalent with mutations involving the forkhead domain.
  
  
  CONCLUSIONS
  Normal corneal development is dependent on the precise dose and levels of activity of certain forkhead transcription factors. The altered corneal thickness attributable to increased forkhead gene dosage is particularly important, because it may affect the clinical management of certain glaucoma subtypes and lead to excessive treatment. The FOXC1 and Foxe3 data, taken together with the novel ocular phenotypes of FOXC2 mutations, highlight the remarkable cross-species conservation of function among forkhead genes.
authors.affiliation: Department of Molecular Genetics, Institute of Ophthalmology, London, United Kingdom. ojlehmann@yahoo.com
authors.forename: Ordan J
authors.initials: OJ
authors.lastname: Lehmann
authors.forename: Stephen
authors.initials: S
authors.lastname: Tuft
authors.forename: Glen
authors.initials: G
authors.lastname: Brice
authors.forename: Richard
authors.initials: R
authors.lastname: Smith
authors.forename: Asa
authors.initials: A
authors.lastname: Blixt
authors.forename: Rachel
authors.initials: R
authors.lastname: Bell
authors.forename: Bengt
authors.initials: B
authors.lastname: Johansson
authors.forename: Tim
authors.initials: T
authors.lastname: Jordan
authors.forename: Roger A
authors.initials: RA
authors.lastname: Hitchings
authors.forename: Peng T
authors.initials: PT
authors.lastname: Khaw
authors.forename: Simon W M
authors.initials: SW
authors.lastname: John
authors.forename: Peter
authors.initials: P
authors.lastname: Carlsson
authors.forename: Shomi S
authors.initials: SS
authors.lastname: Bhattacharya
mesh_terms: D000818:Animals; D000869:Anterior Eye Segment / Q000002:abnormalities* / Q000473:pathology; D003315:Cornea / Q000002:abnormalities / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005124:Eye Abnormalities / Q000235:genetics* / Q000473:pathology; D051858:Forkhead Transcription Factors; D005901:Glaucoma / Q000235:genetics*; D006801:Humans; D007429:Intraocular Pressure / Q000235:genetics; D007498:Iris / Q000002:abnormalities / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; C112743:FOXC1 protein, human; C404285:FOXE3 protein, human; D051858:Forkhead Transcription Factors; C112890:Foxc1 protein, mouse; C498612:Foxe3 protein, mouse; D014157:Transcription Factors; C082078:mesenchyme fork head 1 protein