Replication and refinement of linkage of posterior polymorphous corneal dystrophy to the posterior polymorphous corneal dystrophy 1 locus on chromosome 20

Yellore, Vivek S.; Papp, Jeanette C.; Sobel, Eric M.; Khan, Mohammed; Rayner, Sylvia A.; Farber, Débora B.; Aldave, Anthony J.

doi:10.1097/gim.0b013e31803c4dc2

Cited by 21 publications

(31 citation statements)

References 14 publications

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“…[18, 24] Screening of the 1.8 kb region upstream of the translational start site of OVOL2 in the remaining 26 PPCD probands in whom a ZEB1 truncating mutation was not identified revealed five different heterozygous variants in eight probands, while the remaining 18 probands did not demonstrate any heterozygous variants within either the OVOL2 promoter or 5’ UTR (Table 1). Of the five identified variants, only one, c.-61G>A, was either novel or rare (MAF ≤ 0.01).…”

Section: Resultsmentioning

confidence: 99%

“…[24, 25] We identified the same c.-307T>C variant within affected members of the family that Heon and colleagues mapped to the PPCD1 locus as in the family that we subsequently mapped to an overlapping interval. [13, 18] Although the c.-307T>C was found in two unaffected family members (VI-3 and VI-4), these two individuals were first evaluated in their twenties and were not available for re-examination. Therefore, their affected status cannot be confirmed.…”

Section: Discussionmentioning

confidence: 99%

“…The custom array was designed for the interrogation of: a 16.7 Mb region (hg19: 17.3 Mb– 34.0 Mb) on chromosome 20 encompassing the refined PPCD1 interval and approximately 2.7Mb (0.54 Mb 5’ and 2.17 Mb 3’) of flanking sequence; and a 5.2 Mb region (hg19: 29.1Mb– 34.3 Mb) on chromosome 10 containing the ZEB1 gene (31.6 Mb– 31.8 Mb) and 5 Mb (2.5 Mb 5’ and 2.5 Mb 3’) of flanking sequence. [18] The array utilized 52,828 oligonucleotide probes spread over the two loci. Data analysis was performed using the Agilent CytoGenomics 3.0 software.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

et al. 2017

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“…[5] Although the necessity for keratoplasty differs in various cohorts of PPCD patients (it can be as high as 40%)[16] and a large majority of affected individuals are asymptomatic till an older age, many PPCD patients are younger at the time of grafting[12] than patients with late-onset Fuchs endothelial corneal dystrophy which is also treated with DMEK and DMEK-S.[45] Therefore, all possible benefits as well as disadvantages of various keratoplasty surgical techniques need to be very carefully evaluated.…”

Section: Discussionmentioning

confidence: 99%

Descemet membrane endothelial keratoplasty with a stromal rim in the treatment of posterior polymorphous corneal dystrophy

Studený

Jirsová

Kuchynka

et al. 2012

Indian J Ophthalmol

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A 20-year-old patient, diagnosed with posterior polymorphous corneal dystrophy, developed corneal edema for which he underwent Descemet membrane endothelial keratoplasty with a stromal rim (DMEK-S) in the right eye. No intra- or postoperative complications were noted. At the last follow-up 2 years and 9 months after the procedure, the best corrected visual acuity was 1.0 and endothelial cell density declined from 3533 cells/mm2 to 1012 cells/mm2. Despite the endothelial cell loss, DMEK-S appears to be a good alternative to other surgical techniques for the treatment of corneal endotheliopathies, and it may be of benefit to young patients.

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“…1 Endothelial cells from affected corneas demonstrate characteristics of epithelial cells including the ability to proliferate, leading to focal formation of multilayered areas, and multilamination of Descemet membrane. [2][3][4] PPCD is genetically heterogeneous with three identified loci; PPCD1 (OMIM #122000) on chromosome 20p with a currently undefined causative gene, [5][6][7] PPCD2 (OMIM #609140) associated with mutations in COL8A2, 8 and PPCD3 (OMIM #609141) caused by mutations in ZEB1. 9 To date, over 30 heterozygous nonsense and frameshifting mutations in ZEB1 have been identified.…”

Section: Introductionmentioning

confidence: 99%

Heterozygous deletions at the ZEB1 locus verify haploinsufficiency as the mechanism of disease for posterior polymorphous corneal dystrophy type 3

Lišková

Evans²,

Davidson³

et al. 2015

Eur J Hum Genet

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A substantial proportion of patients with posterior polymorphous corneal dystrophy (PPCD) lack a molecular diagnosis. We evaluated 14 unrelated probands who had a clinical diagnosis of PPCD who were previously determined to be negative for mutations in ZEB1 by direct sequencing. A combination of techniques was used including whole-exome sequencing (WES), single-nucleotide polymorphism (SNP) array copy number variation (CNV) analysis, quantitative real-time PCR, and long-range PCR. Segregation of potentially pathogenic changes with disease was confirmed, where possible, in family members. A putative run of homozygosity on chromosome 10 was identified by WES in a three-generation PPCD family, suggestive of a heterozygous deletion. SNP array genotyping followed by long-range PCR and direct sequencing to define the breakpoints confirmed the presence of a large deletion that encompassed multiple genes, including ZEB1. Identification of a heterozygous deletion spanning ZEB1 prompted us to further investigate potential CNVs at this locus in the remaining probands, leading to detection of two additional heterozygous ZEB1 gene deletions. This study demonstrates that ZEB1 mutations account for a larger proportion of PPCD than previously estimated, and supports the hypothesis that haploinsufficiency of ZEB1 is the underlying molecular mechanism of disease for PPCD3.

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Replication and refinement of linkage of posterior polymorphous corneal dystrophy to the posterior polymorphous corneal dystrophy 1 locus on chromosome 20

Cited by 21 publications

References 14 publications

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

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

Descemet membrane endothelial keratoplasty with a stromal rim in the treatment of posterior polymorphous corneal dystrophy

Heterozygous deletions at the ZEB1 locus verify haploinsufficiency as the mechanism of disease for posterior polymorphous corneal dystrophy type 3

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