title: Mutations in the zinc finger protein gene, ZNF469, contribute to the pathogenesis of keratoconus.
abstract: OBJECTIVE
  Mutations in the zinc finger protein gene ZNF469 cause recessive brittle cornea syndrome, characterized by spontaneous corneal perforations. Genome-wide association studies (GWAS) have implicated common variants in this gene as a determinant for central corneal thickness (CCT). We investigated the contribution of ZNF469 in a sample set of keratoconus patients.
  
  
  METHODS
  Forty-three patients with keratoconus (49% Māori or Pacific [Polynesian]) were recruited. If a family history was present, family members were recruited. Participants underwent comprehensive examination, and a DNA sample was collected. Mutational analysis of ZNF469 was undertaken using Sanger sequencing, including an ancestrally matched Polynesian control population. Bioinformatic databases of exome variation and protein prediction software were used to determine presence and frequency and the pathogenicity for each observed change.
  
  
  RESULTS
  Fourteen nonsynonymous missense single nucleotide polymorphisms (SNPs) were observed in ZNF469. Of the 43 probands, at least one probable disease-causing variant was detected in 20 (46%) (16/32 sporadic, 4/11 familial) and two variants in 5 (11.6%) (3/32 sporadic, 2/11 familial). Only heterozygous changes segregated with disease. Three "deleterious" changes observed in the Polynesian controls were removed from analysis; therefore pathogenic variants occurred in 10/43 (23.3%).
  
  
  CONCLUSIONS
  Rare missense mutations in ZNF469, predicted to be pathogenic, occurred heterozygously, at a frequency of 23% in a keratoconus population. ZNF469 is associated with CCT in GWAS and is therefore likely to play a role in the synthesis and/or organization of corneal collagen fibers. The pathogenic changes observed either genetically predispose toward a "thin" cornea, which then becomes keratoconic, or are directly pathogenic.
authors.affiliation: Department of Ophthalmology, New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Vincent
authors.affiliation: Department of Ophthalmology, New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand.
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Jordan
authors.affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand.
authors.forename: Murray J
authors.initials: MJ
authors.lastname: Cadzow
authors.affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand.
authors.forename: Tony R
authors.initials: TR
authors.lastname: Merriman
authors.affiliation: Department of Ophthalmology, New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand.
authors.forename: Charles N
authors.initials: CN
authors.lastname: McGhee
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007640:Keratoconus / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
chemical_list: D014157:Transcription Factors; C530065:ZNF469 protein, human
keywords: ZNF469; genetics; keratoconus