September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Autosomal dominant corneal endothelial dystrophies CHED1 and PPCD1 are allelic disorders caused by non-coding mutations in the promoter of OVOL2.
Author Affiliations & Notes
  • Alice E Davidson
    UCL Institute of Ophthalmology, London, United Kingdom
  • Petra Liskova
    Department of Ophthalmology, First Faculty of Medicine, Charles University in Prague and General Teaching Hospital in Prague, Prauge, Czech Republic
    Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague , Czech Republic
  • Cerys J Evans
    UCL Institute of Ophthalmology, London, United Kingdom
  • Lubica Dudakova
    Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague , Czech Republic
  • Lenka Nosková
    Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague , Czech Republic
  • Nikolas Pontikos
    UCL Genetics Institute, London, United Kingdom
  • Vincent Plagnol
    UCL Genetics Institute, London, United Kingdom
  • Martin Filipec
    European Eye Clinic Lexum,, Prague , Czech Republic
  • Stanislav Kmoch
    Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague , Czech Republic
  • Stephen J Tuft
    Moorfields Eye Hospital , London, United Kingdom
    UCL Institute of Ophthalmology, London, United Kingdom
  • Alison J Hardcastle
    UCL Institute of Ophthalmology, London, United Kingdom
  • Footnotes
    Commercial Relationships   Alice Davidson, None; Petra Liskova, None; Cerys Evans, None; Lubica Dudakova, None; Lenka Nosková, None; Nikolas Pontikos, None; Vincent Plagnol, None; Martin Filipec, None; Stanislav Kmoch, None; Stephen Tuft, None; Alison Hardcastle, None
  • Footnotes
    Support  Fight for Sight early career investigator award
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 4821. doi:
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      Alice E Davidson, Petra Liskova, Cerys J Evans, Lubica Dudakova, Lenka Nosková, Nikolas Pontikos, Vincent Plagnol, Martin Filipec, Stanislav Kmoch, Stephen J Tuft, Alison J Hardcastle; Autosomal dominant corneal endothelial dystrophies CHED1 and PPCD1 are allelic disorders caused by non-coding mutations in the promoter of OVOL2.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4821.

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

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Abstract

Purpose : Congenital hereditary endothelial dystrophy 1 (CHED1) and posterior polymorphous corneal dystrophy 1 (PPCD1) are autosomal dominant inherited corneal endothelial disorders that have been genetically mapped to overlapping loci on chromosome 20p. We recruited extensive pedigrees, comprising over 100 affected individuals, with the aim of identifying the genetic cause(s) of disease.

Methods : Targeted and whole genome sequencing (WGS) was performed on multiple individuals from CHED1 and PPCD1 index families. The variant data were filtered according to allele frequency and potential pathogenicity. Candidate variants were directly sequenced for validation and segregation in the extensive pedigrees, and the promoter region of OVOL2 was directly sequenced as a candidate region in additional families. A dual luciferase reporter assay was used to assess the impact of disease-associated mutations on the activity of the OVOL2 promoter.

Results : Following exclusion of coding, splice-site and copy number variations, two unique variants in a conserved region of the OVOL2 promoter were identified, one segregating with CHED1, and another segregating with PPCD1 in the respective index families. Two further unique variants were identified in additional families by direct sequencing. The four unique mutations lie within a highly conserved 100 bp region of the OVOL2 proximal promoter. In vitro analysis using a dual luciferase reporter assay demonstrated that all four OVOL2 promoter mutations exhibited significantly (P≤0.001) increased transcriptional activity compared to the corresponding wild-type promoter sequence.

Conclusions : Our data establishes CHED1 and PPCD1 as allelic conditions, with CHED1 an extreme of what can be considered a disease spectrum, and implicates transcriptional dysregulation of OVOL2 as a common cause of dominantly inherited corneal endothelial dystrophies. OVOL2 encodes ovo-like 2 zinc finger 2, a C2H2 zinc finger transcription factor that regulates mesenchymal to epithelial transition, and acts as a direct transcriptional repressor of the established PPCD-associated gene, ZEB1. We postulate that the mutations identified introduce cryptic cis-acting regulatory sequence binding sites that drive aberrant OVOL2 expression during development of the corneal endothelium.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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