Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus

Abstract

Keratoconus, a common inherited ocular disorder resulting in progressive corneal thinning, is the leading indication for corneal transplantation in the developed world. Genome-wide association studies have identified common SNPs 100 kb upstream of ZNF469 strongly associated with corneal thickness. Homozygous mutations in ZNF469 and PR domain-containing protein 5 (PRDM5) genes result in brittle cornea syndrome (BCS) Types 1 and 2, respectively. BCS is an autosomal recessive generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Some individuals with heterozygous PRDM5 mutations demonstrate a carrier ocular phenotype, which includes a mildly reduced corneal thickness, keratoconus and blue sclera. We hypothesized that heterozygous variants in PRDM5 and ZNF469 predispose to the development of isolated keratoconus. We found a significant enrichment of potentially pathologic heterozygous alleles in ZNF469 associated with the development of keratoconus (P = 0.00102) resulting in a relative risk of 12.0. This enrichment of rare potentially pathogenic alleles in ZNF469 in 12.5% of keratoconus patients represents a significant mutational load and highlights ZNF469 as the most significant genetic factor responsible for keratoconus identified to date.

Brittle Cornea Syndrome: Case Report with Novel Mutation in thePRDM5Gene and Review of the Literature

“…Brittle cornea syndrome is a rare autosomal recessive disease with generalized connective tissue damage [1]. Classical ophthalmologic findings include extreme corneal thinning (220–450  μ m) [1], irregular corneal astigmatism, high myopia, blue sclera, progressive keratoglobus or keratoconus, and retinal detachment [1–3].…”

“…Classical ophthalmologic findings include extreme corneal thinning (220–450  μ m) [1], irregular corneal astigmatism, high myopia, blue sclera, progressive keratoglobus or keratoconus, and retinal detachment [1–3]. Mutations in the Zinc-Finger-469 (ZNF469) gene are causative for brittle cornea syndrome type 1, and mutations in the gene for PR-domain-containing protein 5 ( PRDM5 ) determine brittle cornea syndrome type 2 [1–4]. Corneal thickness is strongly associated with ZNF469 and PRDM5 gene products [1, 3, 5].…”

“…Mutations in the Zinc-Finger-469 (ZNF469) gene are causative for brittle cornea syndrome type 1, and mutations in the gene for PR-domain-containing protein 5 ( PRDM5 ) determine brittle cornea syndrome type 2 [1–4]. Corneal thickness is strongly associated with ZNF469 and PRDM5 gene products [1, 3, 5]. It is obscure how mutations in these genes cause typical features of this syndrome, but the gene products, both containing DNA binding zinc finger domains, seem to play a role in the transcriptional regulation of extracellular matrix genes, including corneal fibrillar collagens [5, 6].…”

Positive selection rather than relaxation of functional constraint drives the evolution of vision during chicken domestication

“…Specific examples in this group are ZNF469 and RD3, with selection signals supported by both XP-CLR and Pi, which have vital roles in vision. ZNF469 encodes a zinc-finger protein and mutations in this gene are associated with brittle cornea syndrome and keratoconus, a common inherited ocular disorder resulting in progressive corneal thinning [30,31]. RD3 on the other hand encodes retinal degeneration 3 protein, and mutations in this gene cause Leber congenital amaurosis type 12, a disease that results in photoreceptor degeneration [32].…”

The Genetic Background of Keratoconus: A Review on Keratoconus Genes

“…Although PRDM5 gene mutations have been detect any pathogenic variants [44]. However, Rohrbach et al investigated both these genes and identified a single patient who did not have a mutation in either ZNF469 or PRDM5, suggesting genetic heterogeneity in BCS [45]. An older study suggested the hypothesis that PRDM5 and ZNF469 regulate extracellular matrix organization through similar biochemical mechanisms [46].…”