Confirmation of the OVOL2 Promoter Mutation c.-307T>C in Posterior Polymorphous Corneal Dystrophy 1

Abstract

PurposeTo 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.MethodsThe 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.ResultsOVOL2 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.ConclusionsPreviously 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.

Agenesis of the corpus callosum, developmental delay, autism spectrum disorder, facial dysmorphism, and posterior polymorphous corneal dystrophy associated with ZEB1 gene deletion

“…OVOL2 is a transcription factor, shown to downregulate ZEB1 by suppressing EMT and driving mesenchymal‐to‐epithelial transition (MET) instead. Hence, current evidence suggests that ZEB1 and OVOL2 genes operate in a regulatory feedback loop, leading to PPCD phenotype (Chung et al, ).…”

Transcriptomic Profiling of Posterior Polymorphous Corneal Dystrophy

“…9 As a ZEB1 mutation was not identified in P6, the promoter, 5′ untranslated region (UTR), and coding regions of OVOL2 were screened in P6 using published primers, PCR conditions, and gene region parameters. 29 ZEB1 promoter region sequences were compared to the RefSeqGene sequence (GenBank accession number NG_017048.1), and ZEB1 coding region nucleotide sequences (including the donor and acceptor splice sites) were read manually by comparing to the cDNA sequences for transcript variants 1 (GenBank accession number NM_001128128.2) and 2 (GenBank accession number NM_030751). OVOL2 coding region sequences were compared to the Genbank OVOL2 transcript NM_021220.3, and OVOL2 promoter region sequences were compared to RefSeqGene sequence (GenBank accession number NG_046859.1).…”

Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4

“… 3 , 9 , 10 , 11 Recently, we and others have established that heterozygous regulatory mutations in the promoter of OVOL2 (MIM: 616441 ) cause PPCD1 (MIM: 122000 ). 2 , 12 ZEB1 and OVOL2 control cell state, through regulation of epithelial-to-mesenchymal transition (EMT) and the converse process of mesenchymal-to-epithelial transition (MET), through a mutually inhibitory pathway. 13 , 14 EMT and MET are central processes in development, and these finely tuned and reversible cell state transition pathways also support the maintenance of cellular identity and function.…”