Association of a Chromosomal Rearrangement Event with Mouse Posterior Polymorphous Corneal Dystrophy and Alterations in Csrp2bp, Dzank1, and Ovol2 Gene Expression

Shen, Anna L.; Moran, Susan A.; Glover, Edward; Drinkwater, Norman R.; Swearingen, Rebecca; Teixeira, Leandro; Bradfield, Christopher A.

doi:10.1371/journal.pone.0157577

Cited by 6 publications

(8 citation statements)

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“…While it is possible that the identified genetic rearrangement leads to PPCD1 in the mouse through upregulation of Ovol2 expression, as is the case in humans, the authors provide compelling evidence for the disruption of Csrp2bp as being causative for PPCD1 in the mouse. [28, 29] However, we did not detect CNV involving the human ortholog CSRP2BP in any of the 8 probands analyzed for CNV. Although identification of other affected pedigrees of sufficient size to perform whole exome sequencing and CNV analysis to identify additional genetic loci should be performed, we also plan to perform and encourage other investigators to perform sequencing of presumed OVOL2 and ZEB1 regulatory sequences to identify other potentially pathogenic sequence variants.…”

Section: Discussionmentioning

confidence: 64%

“…In the PPCD mouse, a chromosomal inversion flanked by deletions involving Csrp2bp and Dzank1 has been identified in the portion of chromosome 2 that is syntenic to the human PPCD1 locus. [28, 29] The investigators reported the upregulation of two Csrp2bp fusion transcripts and Ovol2 , which is located 37 kb from Csrp2bp and 66 kb from the breakpoint of the chromosomal inversion. While it is possible that the identified genetic rearrangement leads to PPCD1 in the mouse through upregulation of Ovol2 expression, as is the case in humans, the authors provide compelling evidence for the disruption of Csrp2bp as being causative for PPCD1 in the mouse.…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…The literature suggests a wide overlap between signatures in terms of gene functions (cell growth, division, small RNA metabolism, protein synthesis, maturation and transport, and mitochondrial dysfunction). In the case of signature C1 (most genes down-regulated), the literature suggested NOP56 (a core component of the small nucleolar ribonucleic protein) as a central element in the signature; interacting with MKKS, NAA20 and PTPRA (genes with roles on mitotic division); ESF1, SNRPB, SNRPB2, POLR3F and CRNKL1 (involved in small RNA processing), PCNA and ITPA (involved correct DNA replication and repair), UBOX5, RRBP1 , RBCK1 and NRSN2 (protein synthesis, maturation and antigen presentation), RBBPP9 (resistance to growth inhibition of TGF); SIRPA and DSTN (cell adhesion) 30–33 . In the signature C1, NOP56 could be a candidate for future therapeutic intervention.…”

Section: Discussionmentioning

confidence: 99%

Multi-omic signatures identify pan-cancer classes of tumors beyond tissue of origin

Gonzalez-Reymundez

Vázquez

2019

Preprint

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7Despite recent advances in treatment, cancer continues to be one of the most lethal human 8 maladies. One of the challenges of cancer treatment is the extreme diversity among seemingly 9 identical tumors: while some tumors may have good prognosis and are treatable, others are quite 10 aggressive, and may lack of effective therapies. Most of this variability comes from wide-spread 11 mutations and epigenetic alterations. Using a novel omic-integration method, we have exploited 12 this molecular information to re-classify tumors beyond the constraints of cell type. Eight novel 13 tumor groups (C1-8) emerged, characterized by unique cancer signatures. C3 had better prognosis, 14 genome stability, and immune infiltration. C2 and C5 had higher genome instability and poorer 15 clinical outcomes. Remaining clusters were characterized by worse outcomes, along with higher 16 genome instability. C1, C7, and C8 were upregulated for cellular and mitochondrial translation, 17 and relatively low proliferation. C6 and C4 were also downregulated for cellular and mitochondrial 18 translation, and had high proliferation rates. C4 was represented by copy losses on chromosome 19 6, and had the highest number of metastatic samples. C8 was characterized by copy losses on 20 chromosome 11, having also the lowest lymphocytic infiltration rate. C6 had the lowest natural 21 killer infiltration rate and was represented by copy gains of genes in chromosome 11. C7 was 22 represented by copy gains on chromosome 6, and had the highest upregulation in mitochondrial 23 translation. We believe that, since molecularly alike tumors could respond similarly to treatment, 24 our results could inform therapeutic action. 25 Significance 26 Cancer has been traditionally studied as a family of different diseases from different anatomical 27 sites. Nevertheless, regardless of the tissue of origin, cancer can be characterized by molecular 28 alterations on mechanisms controlling cell fate and progression. In this study, we integrate 33 29 cancer types and show the existence of eight clusters with unique genomic signatures and clinical 30 characteristics, beyond the site of origin of the tumor. The study and treatment of cancer, based on 31 predominant molecular features, rather than site of origin, can potentially aid in the discovery of 32 novel therapeutic alternatives.33

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“…The PPCD1 mouse exhibits many features of human posterior polymorphous corneal dystrophy, including corneal endothelial cell metaplasia and proliferation and inappropriate pan-cytokeratin expression [ 15 ]. We have shown that mouse PPCD1 is linked to a 3.9 Mbp chromosomal inversion, flanked by 81 Kbp and 542 bp deletions, and located in a region of mouse Chromosome 2 syntenic to the human PPCD1 locus [ 16 ], referred to as Ppcd1 (Mouse Genome Informatics, http://www.informatics.jax.org/ [ 17 ]). This chromosomal rearrangement truncates the coding sequences of two genes, Csrp2bp and Dzank1 , and results in production of novel truncated and fusion transcripts as well as upregulation of the adjacent gene, Ovol2 .…”

Section: Introductionmentioning

confidence: 99%

“…Anterior chamber phenotypes of the PPCD1 mouse on the DBA/2J background (D2.129(B6)- Ppcd1 /J, hereafter referred to as D2. Ppcd1 ) have been described [ 15 , 16 ]. Briefly, D2.…”

Section: Introductionmentioning

confidence: 99%

Retinal pathology in the PPCD1 mouse

et al. 2017

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Retinal phenotypes of the PPCD1 mouse, a mouse model of posterior polymorphous corneal dystrophy, have been characterized. PPCD1 mice on the DBA/2J background (D2.Ppcd1) have previously been reported to develop an enlarged anterior chamber due to epithelialization and proliferation of the corneal endothelium and subsequent blockage of the iridocorneal angle. Results presented here show that D2.Ppcd1 mice develop increased intraocular pressure (IOP), with measurements at three months of age revealing significant increases in IOP. Significant retinal ganglion cell layer cell loss is observed at five months of age. D2.Ppcd1 animals also exhibit marked degeneration of the outer nuclear layer in association with hyperplasia of the retinal pigment epithelium. Evidence of retinal detachment is present as early as three weeks of age. By 3.5 months of age, focal areas of outer nuclear layer loss are observed. Although the GpnmbR150X mutation leads to increased IOP and glaucoma in DBA/2J mice, development of anterior segment and retinal defects in D2.Ppcd1 animals does not depend upon presence of the GpnmbR150X mutation.

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Association of a Chromosomal Rearrangement Event with Mouse Posterior Polymorphous Corneal Dystrophy and Alterations in Csrp2bp, Dzank1, and Ovol2 Gene Expression

Cited by 6 publications

References 39 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

Multi-omic signatures identify pan-cancer classes of tumors beyond tissue of origin

Retinal pathology in the PPCD1 mouse

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