title: Confirmation of the OVOL2 Promoter Mutation c.-307T>C in Posterior Polymorphous Corneal Dystrophy 1.
abstract: OBJECTIVE
  To identify the genetic basis of posterior polymorphous corneal dystrophy (PPCD) in families mapped to the PPCD1 locus and in affected individuals without ZEB1 coding region mutations.
  
  
  METHODS
  The promoter, 5' UTR, and coding regions of OVOL2 was screened in the PPCD family in which linkage analysis established the PPCD1 locus and in 26 PPCD probands who did not harbor a ZEB1 mutation. Copy number variation (CNV) analysis in the PPCD1 and PPCD3 intervals was performed on DNA samples from eight probands using aCGH. Luciferase reporter assays were performed in human corneal endothelial cells to determine the impact of the identified potentially pathogenic variants on OVOL2 promoter activity.
  
  
  RESULTS
  OVOL2 mutation analysis in the first PPCD1-linked family demonstrated segregation of the c.-307T>C variant with the affected phenotype. In the other 26 probands screened, one heterozygous coding region variant and five promoter region heterozygous variants were identified, though none are likely pathogenic based on allele frequency. Array CGH in the PPCD1 and PPCD3 loci excluded the presence of CNV involving either OVOL2 or ZEB1, respectively. The c.-307T>C variant demonstrated increased promoter activity in corneal endothelial cells when compared to the wild-type sequence as has been demonstrated previously in another cell type.
  
  
  CONCLUSIONS
  Previously identified as the cause of PPCD1, the OVOL2 promoter variant c.-307T>C was herein identified in the original family that established the PPCD1 locus. However, the failure to identify presumed pathogenic coding or non-coding OVOL2 or ZEB1 variants, or CNV involving the PPCD1 and PPCD3 loci in 26 other PPCD probands suggests that other genetic loci may be involved in the pathogenesis of PPCD.
authors.affiliation: Stein Eye Institute, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Doug D
authors.identifier: http://orcid.org/0000-0002-8505-9495
authors.initials: DD
authors.lastname: Chung
authors.affiliation: Stein Eye Institute, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Ricardo F
authors.initials: RF
authors.lastname: Frausto
authors.affiliation: Stein Eye Institute, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Aleck E
authors.initials: AE
authors.lastname: Cervantes
authors.affiliation: Stein Eye Institute, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Gee
authors.affiliation: Stein Eye Institute, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Marina
authors.initials: M
authors.lastname: Zakharevich
authors.affiliation: Stein Eye Institute, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Evelyn M
authors.initials: EM
authors.lastname: Hanser
authors.affiliation: Department of Ophthalmology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.affiliation: Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Elise
authors.initials: E
authors.lastname: Heon
authors.affiliation: Stein Eye Institute, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Aldave
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D002460:Cell Line; D020090:Chromosome Segregation / Q000235:genetics; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D005190:Family; D005260:Female; D056426:Genetic Loci; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011401:Promoter Regions, Genetic; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000235:genetics*; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics
chemical_list: D020121:5' Untranslated Regions; C544941:Ovol2 protein, human; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1