title: Autosomal-Dominant Corneal Endothelial Dystrophies CHED1 and PPCD1 Are Allelic Disorders Caused by Non-coding Mutations in the Promoter of OVOL2.
abstract: Congenital hereditary endothelial dystrophy 1 (CHED1) and posterior polymorphous corneal dystrophy 1 (PPCD1) are autosomal-dominant corneal endothelial dystrophies that have been genetically mapped to overlapping loci on the short arm of chromosome 20. We combined genetic and genomic approaches to identify the cause of disease in extensive pedigrees comprising over 100 affected individuals. After exclusion of pathogenic coding, splice-site, and copy-number variations, a parallel approach using targeted and whole-genome sequencing facilitated the identification of pathogenic variants in a conserved region of the OVOL2 proximal promoter sequence in the index families (c.-339_361dup for CHED1 and c.-370T>C for PPCD1). Direct sequencing of the OVOL2 promoter in other unrelated affected individuals identified two additional mutations within the conserved proximal promoter sequence (c.-274T>G and c.-307T>C). OVOL2 encodes ovo-like 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. Interestingly, we did not detect OVOL2 expression in the normal corneal endothelium. Our in vitro data demonstrate that all four mutated OVOL2 promoters exhibited more transcriptional activity than the corresponding wild-type promoter, and we postulate that the mutations identified create cryptic cis-acting regulatory sequence binding sites that drive aberrant OVOL2 expression during endothelial cell development. Our data establish CHED1 and PPCD1 as allelic conditions and show that CHED1 represents the extreme of what can be considered a disease spectrum. They also implicate transcriptional dysregulation of OVOL2 as a common cause of dominantly inherited corneal endothelial dystrophies.
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Alice E
authors.initials: AE
authors.lastname: Davidson
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Ke Karlovu 2, Prague 128 08, Czech Republic; Department of Ophthalmology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, U Nemocnice 2, Prague 128 08, Czech Republic. Electronic address: petra.liskova@lf1.cuni.cz.
authors.forename: Petra
authors.initials: P
authors.lastname: Liskova
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Cerys J
authors.initials: CJ
authors.lastname: Evans
authors.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Ke Karlovu 2, Prague 128 08, Czech Republic.
authors.forename: Lubica
authors.initials: L
authors.lastname: Dudakova
authors.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Ke Karlovu 2, Prague 128 08, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Nosková
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; UCL Genetics Institute, University College London, London WC1E 6BT, UK.
authors.forename: Nikolas
authors.initials: N
authors.lastname: Pontikos
authors.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Ke Karlovu 2, Prague 128 08, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Hartmannová
authors.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Ke Karlovu 2, Prague 128 08, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Hodaňová
authors.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Ke Karlovu 2, Prague 128 08, Czech Republic.
authors.forename: Viktor
authors.initials: V
authors.lastname: Stránecký
authors.affiliation: Institute of Molecular Genetics, Vídeňská 1083, Prague 142 20, Czech Republic.
authors.forename: Zbyněk
authors.initials: Z
authors.lastname: Kozmík
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Levis
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Nwamaka
authors.initials: N
authors.lastname: Idigo
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Sasai
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Maher
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: James
authors.initials: J
authors.lastname: Bellingham
authors.affiliation: Moorfields Eye Hospital, London EC1V 2PD, UK.
authors.forename: Neyme
authors.initials: N
authors.lastname: Veli
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Neil D
authors.initials: ND
authors.lastname: Ebenezer
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Julie T
authors.initials: JT
authors.lastname: Daniels
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
authors.forename: Caroline M H
authors.initials: CM
authors.lastname: Thaung
authors.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Ke Karlovu 2, Prague 128 08, Czech Republic.
authors.forename: Katerina
authors.initials: K
authors.lastname: Jirsova
authors.affiliation: UCL Genetics Institute, University College London, London WC1E 6BT, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: European Eye Clinic Lexum, Antala Staška 1670/80, Prague 140 00, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Filipec
authors.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Ke Karlovu 2, Prague 128 08, Czech Republic.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Kmoch
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tuft
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK. Electronic address: a.hardcastle@ucl.ac.uk.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Hardcastle
mesh_terms: D000483:Alleles; D001483:Base Sequence; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics*; D004247:DNA; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D011401:Promoter Regions, Genetic; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C544941:Ovol2 protein, human; D014157:Transcription Factors; D004247:DNA