title: Screening the visual system homeobox 1 gene in keratoconus and posterior polymorphous dystrophy cohorts identifies a novel variant.
abstract: OBJECTIVE
  Mutations in the visual system homeobox 1 (VSX1) gene have been described at a low frequency in keratoconus and posterior polymorphous corneal dystrophy (PPCD). The putative role is controversial for several reasons, including a lack of mutations detected in other population cohorts. This study aims to determine whether VSX1 contributes to the genetic pathogenesis of keratoconus and PPCD in a New Zealand population, and includes analysis of a Polynesian population.
  
  
  METHODS
  Recruitment of patients with keratoconus and PPCD, comprehensive clinical examination including corneal topography and pachymetry, and collection of biologic samples for DNA extraction were undertaken. Mutational analysis of VSX1 (exons 1-7) with PCR and sequencing with bioinformatic assessment of variants was performed. Probable pathogenic variants were screened for in a control population using high-resolution melting analysis.
  
  
  RESULTS
  Forty-seven patients with keratoconus, including 15 familial cases, and ten unrelated patients with PPCD were recruited. Two pathogenic changes were detected; a novel change c.173C>T (p.Pro58Leu) was found in a patient with PPCD, predicted to be pathogenic, and not seen in 200 ethnically matched control alleles. The previously reported c.731A>G (p.His244Arg) was detected in a patient with sporadic keratoconus, and not present in the controls. No family members were available for segregation analysis.
  
  
  CONCLUSIONS
  This study reports the presence of pathogenic mutations in VSX1 in PPCD and keratoconus, including a novel disease-causing variant. The affected numbers are small, but given the growing body of evidence of pathogenic segregating changes in VSX1 in disease cohorts, the expression in keratocytes as part of wound healing, and the documented association of PPCD and keratoconus, it seems likely that the role of VSX1 as a genetic factor contributing to disease is real.
authors.affiliation: Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Science, University of Auckland, New Zealand. a.vincent@auckland.ac.nz
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Vincent
authors.forename: Charlotte
authors.initials: C
authors.lastname: Jordan
authors.forename: Leo
authors.initials: L
authors.lastname: Sheck
authors.forename: Rachel
authors.initials: R
authors.lastname: Niederer
authors.forename: Dipika V
authors.initials: DV
authors.lastname: Patel
authors.forename: Charles N J
authors.initials: CN
authors.lastname: McGhee
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D015331:Cohort Studies; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics*; D003710:Demography; D004587:Electrophoresis, Agar Gel; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007640:Keratoconus / Q000235:genetics*; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009691:Nucleic Acid Denaturation / Q000235:genetics; D055815:Young Adult
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; C491583:VSX1 protein, human