Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus
| Autor: | Daniel F. Schorderet, David J. Armstrong, Veronique Vitart, Chris F. Inglehearn, Graeme C.M. Black, Aine Rice, Louise F. Porter, Francis L. Munier, Forbes D C Manson, Alan F. Wright, David Simpson, Judith Lechner, Colin E. Willoughby |
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| Rok vydání: | 2014 |
| Předmět: |
Joint Instability
Heterozygote Keratoconus Pathology medicine.medical_specialty genetic structures medicine.medical_treatment Genome-wide association study Single-nucleotide polymorphism Biology Polymorphism Single Nucleotide Cornea Genetics medicine Humans Eye Abnormalities Allele Molecular Biology Genetic Association Studies Genetics (clinical) Corneal transplantation Association Studies Articles Homozygote Heterozygote advantage General Medicine medicine.disease eye diseases 3. Good health DNA-Binding Proteins medicine.anatomical_structure Ehlers–Danlos syndrome Mutation Skin Abnormalities Ehlers-Danlos Syndrome sense organs Transcription Factors |
| Zdroj: | Human Molecular Genetics, vol. 23, no. 20, pp. 5527-35 |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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