September 2014
Volume 55, Issue 9
Research Highlight  |   September 2014
Heterozygous Coding ZNF469 Variants Enriched in New Zealand Patients With Isolated Keratoconus
Investigative Ophthalmology & Visual Science September 2014, Vol.55, 5636. doi:10.1167/iovs.14-15486
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      Elfride De Baere; Heterozygous Coding ZNF469 Variants Enriched in New Zealand Patients With Isolated Keratoconus. Invest. Ophthalmol. Vis. Sci. 2014;55(9):5636. doi: 10.1167/iovs.14-15486.

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      © ARVO (1962-2015); The Authors (2016-present)

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Keratoconus (Online Mendelian Inheritance of Man [MIM] 148300) is a common bilateral ocular disease characterized by progressive corneal thinning and ectasia. The progressive corneal thinning (mean central corneal thickness [CCT]) results in myopia and corneal astigmatism. Genome-wide association studies (GWAS) in different populations have showed that common noncoding single nucleotide polymorphisms (SNPs) of zinc finger 469 (ZNF469 [MIM 612078]) are strongly associated with CCT. 1,2 Moreover homozygous mutations in ZNF469 lead to brittle cornea syndrome type 1 (BCS1 [MIM 229200]), a rare autosomal recessive connective tissue disease associated with abnormal thin corneas. 3 Since homozygous ZNF469 mutations result in a corneal thinning disorder, and since common SNPs 100-kb upstream of ZNF469 are strongly associated with CCT, Vincent et al. 4 hypothesized that heterozygous variants in ZNF469 might predispose to the development of isolated keratoconus. Therefore, the coding regions of ZNF469 were investigated in 43 patients from New Zealand (one-half of which are Maori or Polynesian) with isolated keratoconus. Potentially pathogenic missense variants were found in 23% of this population. Interestingly, the current study converges well with a recent study by Lechner et al. 5 revealing heterozygous coding variants in ZNF469 in 12.5% of three European cohorts with isolated keratoconus (two from the United Kingdom, and one from Switzerland, respectively), representing a significant enrichment of ZNF469 heterozygous alleles (P = 0.00102). In conclusion, the enrichment of rare mutations in ZNF469 in a New Zealand population with keratoconus uncovers, for the first time, coding ZNF469 alleles as potentially important genetic factors contributing to the pathogenesis of keratoconus. 
Lu Y Dimasi DP Hysi PG Common genetic variants near the Brittle Cornea Syndrome locus ZNF469 influence the blinding disease risk factor central corneal thickness. PLoS Genet . 2010; 13: e1000947. [CrossRef]
Lu Y Vitart V Burdon KP Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus. Nat Genet . 2013; 45: 155–163. [CrossRef] [PubMed]
Abu A Frydman M Marek D Deleterious mutations in the zinc-finger 469 gene cause Brittle Cornea Syndrome. Am J Hum Genet . 2008; 82: 1217–1222. [CrossRef] [PubMed]
Vincent AL Jordan CA Cadzow MJ Merriman TR McGhee CN. Mutations in the zinc finger protein gene, ZNF469, contribute to the pathogenesis of keratoconus. Invest Ophthalmol Vis Sci . 2014; 55: 5629–5635. [CrossRef] [PubMed]
Lechner J Porter LF Rice A Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus [ published online ahead of print June 3, 2014]. Hum Mol Genet . doi:10.1093/hmg/ddu253 .
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