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Andrea Vincent, Charlotte Jordan, Bryan Hay, Amanda Richards, Charles McGhee; Mutations in the zinc finger protein gene, ZNF469 contribute to the pathogenesis of keratoconus. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4069. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Mutations in the zinc finger protein gene ZNF469 are identified as one genetic cause for the recessive disorder Brittle Cornea syndrome, characterised by spontaneous corneal perforations. GWAS studies have also implicated this gene as a determinant for central corneal thickness(CCT). We investigated the genetic contribution of ZNF469 in a cohort of patients with keratoconus - both familial and sporadic.
Patients with keratoconus were identified and recruited from the University of Auckland special eye clinic, and the Eye Department, Auckland District Health Board. If a family history of keratoconus was present, family members were recruited and examined where possible. Following informed consent, all individuals underwent comprehensive anterior segment examination including corneal topography (Orbscan, Pentacam) and axial length, and a biological sample (venous blood, saliva) collected for DNA extraction. Mutational analysis of both exons of ZNF469 was undertaken using polymerase chain reaction, bidirectional Sanger sequencing, and high resolution melting analysis. 4 changes detected in the familial cases (Polynesian) were screened in an ethnically matched population. For each observed change, bioinformatic databases of exome variation were used to determine presence and frequency, and protein prediction software to determine pathogenicity.
Of the 43 probands, at least one probable disease causing variant was detected in ZNF469 in 20 (46%), and in 5, two variants were observed (11.6% - 4 compound heterozygotes, 1 homozygote). Fourteen non-synonymous missense SNPs were observed, 6 of which were not previously documented in any population-based genetic variant database. For the sporadic cases, 12/32 had one change, and 3/32, 2 changes. Of the familial cases 3/11 probands had one change, and 2 of the 11 had 2 changes, although only heterozygous changes segregated with disease.
Rare missense mutations in ZNF469, predicted to be pathogenic, are found heterozygously at a frequency of 46% in a keratoconus population. ZNF469 is shown to be associated with CCT, and likely to play a role in the synthesis and/or organization of corneal collagen fibres. The findings in this cohort suggest the pathogenic changes observed either genetically predispose towards a “thin” cornea, which then becomes keratoconic, or are directly pathogenic.
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