The PPCD1 Mouse: Characterization of a Mouse Model for Posterior Polymorphous Corneal Dystrophy and Identification of a Candidate Gene

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2010 Sep 3

PMID 20808945

Citations 5

Authors

Anna L Shen

Kathleen A OLeary

Richard R Dubielzig

Norman Drinkwater

Christopher J Murphy

Charles B Kasper

Christopher A Bradfield

Affiliations

Soon will be listed here.

Abstract

The PPCD1 mouse, a spontaneous mutant that arose in our mouse colony, is characterized by an enlarged anterior chamber resulting from metaplasia of the corneal endothelium and blockage of the iridocorneal angle by epithelialized corneal endothelial cells. The presence of stratified multilayered corneal endothelial cells with abnormal patterns of cytokeratin expression are remarkably similar to those observed in human posterior polymorphous corneal dystrophy (PPCD) and the sporadic condition, iridocorneal endothelial syndrome. Affected eyes exhibit epithelialized corneal endothelial cells, with inappropriate cytokeratin expression and proliferation over the iridocorneal angle and posterior cornea. We have termed this the "mouse PPCD1" phenotype and mapped the mouse locus for this phenotype, designated "Ppcd1", to a 6.1 Mbp interval on Chromosome 2, which is syntenic to the human Chromosome 20 PPCD1 interval. Inheritance of the mouse PPCD1 phenotype is autosomal dominant, with complete penetrance on the sensitive DBA/2J background and decreased penetrance on the C57BL/6J background. Comparative genome hybridization has identified a hemizygous 78 Kbp duplication in the mapped interval. The endpoints of the duplication are located in positions that disrupt the genes Csrp2bp and 6330439K17Rik and lead to duplication of the pseudogene LOC100043552. Quantitative reverse transcriptase-PCR indicates that expression levels of Csrp2bp and 6330439K17Rik are decreased in eyes of PPCD1 mice. Based on the observations of decreased gene expression levels, association with ZEB1-related pathways, and the report of corneal opacities in Csrp2bp(tm1a(KOMP)Wtsi) heterozygotes and embryonic lethality in nulls, we postulate that duplication of the 78 Kbp segment leading to haploinsufficiency of Csrp2bp is responsible for the mouse PPCD1 phenotype. Similarly, CSRP2BP haploinsufficiency may lead to human PPCD.

Citing Articles

Animal models of corneal endothelial dysfunction to facilitate development of novel therapies.

Park S, Leonard B, Raghunathan V, Kim S, Li J, Mannis M Ann Transl Med. 2021; 9(15):1271.

PMID: 34532408 PMC: 8421955. DOI: 10.21037/atm-20-4389.

Retinal pathology in the PPCD1 mouse.

Shen A, Moran S, Glover E, Teixeira L, Bradfield C PLoS One. 2017; 12(10):e0185094.

PMID: 28981549 PMC: 5628829. DOI: 10.1371/journal.pone.0185094.

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

Chung D, Frausto R, Cervantes A, Gee K, Zakharevich M, Hanser E PLoS One. 2017; 12(1):e0169215.

PMID: 28046031 PMC: 5207508. DOI: 10.1371/journal.pone.0169215.

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

Shen A, Moran S, Glover E, Drinkwater N, Swearingen R, Teixeira L PLoS One. 2016; 11(6):e0157577.

PMID: 27310661 PMC: 4910986. DOI: 10.1371/journal.pone.0157577.

Genetics of the corneal endothelial dystrophies: an evidence-based review.

Aldave A, Han J, Frausto R Clin Genet. 2013; 84(2):109-19.

PMID: 23662738 PMC: 3885339. DOI: 10.1111/cge.12191.

References

Chow R, Volgyi B, Szilard R, Ng D, McKerlie C, Bloomfield S . Control of late off-center cone bipolar cell differentiation and visual signaling by the homeobox gene Vsx1. Proc Natl Acad Sci U S A. 2004; 101(6):1754-9. PMC: 341848. DOI: 10.1073/pnas.0306520101. View

Haider N, Ikeda A, Naggert J, Nishina P . Genetic modifiers of vision and hearing. Hum Mol Genet. 2002; 11(10):1195-206. DOI: 10.1093/hmg/11.10.1195. View

Hopfer U, Fukai N, Hopfer H, Wolf G, Joyce N, Li E . Targeted disruption of Col8a1 and Col8a2 genes in mice leads to anterior segment abnormalities in the eye. FASEB J. 2005; 19(10):1232-44. DOI: 10.1096/fj.04-3019com. View

Shen A, OLeary K, Kasper C . Association of multiple developmental defects and embryonic lethality with loss of microsomal NADPH-cytochrome P450 oxidoreductase. J Biol Chem. 2001; 277(8):6536-41. DOI: 10.1074/jbc.M111408200. View

Cockerham G, Laver N, Hidayat A, McCoy D . An immunohistochemical analysis and comparison of posterior polymorphous dystrophy with congenital hereditary endothelial dystrophy. Cornea. 2002; 21(8):787-91. DOI: 10.1097/00003226-200211000-00012. View

Hidayat A, Cockerham G . Epithelial metaplasia of the corneal endothelium in Fuchs endothelial dystrophy. Cornea. 2006; 25(8):956-9. DOI: 10.1097/01.ico.0000228786.84581.ee. View

Lefebvre V, Sowka J, Frauens B . The clinical spectrum between posterior polymorphous dystrophy and iridocorneal endothelial syndromes. Optometry. 2009; 80(8):431-6. DOI: 10.1016/j.optm.2009.02.009. View

Gottsch J, Sundin O, Liu S, Jun A, Broman K, Stark W . Inheritance of a novel COL8A2 mutation defines a distinct early-onset subtype of fuchs corneal dystrophy. Invest Ophthalmol Vis Sci. 2005; 46(6):1934-9. DOI: 10.1167/iovs.04-0937. View

Wang Y, Faiola F, Xu M, Pan S, Martinez E . Human ATAC Is a GCN5/PCAF-containing acetylase complex with a novel NC2-like histone fold module that interacts with the TATA-binding protein. J Biol Chem. 2008; 283(49):33808-15. PMC: 2590711. DOI: 10.1074/jbc.M806936200. View

10.

Jirsova K, Merjava S, Martincova R, Gwilliam R, Ebenezer N, Liskova P . Immunohistochemical characterization of cytokeratins in the abnormal corneal endothelium of posterior polymorphous corneal dystrophy patients. Exp Eye Res. 2007; 84(4):680-6. DOI: 10.1016/j.exer.2006.12.006. View

11.

Aldave A, Yellore V, Yu F, Bourla N, Sonmez B, Salem A . Posterior polymorphous corneal dystrophy is associated with TCF8 gene mutations and abdominal hernia. Am J Med Genet A. 2007; 143A(21):2549-56. DOI: 10.1002/ajmg.a.31978. View

12.

Yellore V, Rayner S, Emmert-Buck L, Tabin G, Raber I, Hannush S . No pathogenic mutations identified in the COL8A2 gene or four positional candidate genes in patients with posterior polymorphous corneal dystrophy. Invest Ophthalmol Vis Sci. 2005; 46(5):1599-603. DOI: 10.1167/iovs.04-1321. View

13.

Aldave A, Yellore V, Vo R, Kamal K, Rayner S, Plaisier C . Exclusion of positional candidate gene coding region mutations in the common posterior polymorphous corneal dystrophy 1 candidate gene interval. Cornea. 2009; 28(7):801-7. PMC: 2714875. DOI: 10.1097/ICO.0b013e31819672fb. View

14.

Hosseini S, Herd S, Vincent A, Heon E . Genetic analysis of chromosome 20-related posterior polymorphous corneal dystrophy: genetic heterogeneity and exclusion of three candidate genes. Mol Vis. 2008; 14:71-80. PMC: 2267740. View

15.

Nagy A, Rossant J, Nagy R, Abramow-Newerly W, Roder J . Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc Natl Acad Sci U S A. 1993; 90(18):8424-8. PMC: 47369. DOI: 10.1073/pnas.90.18.8424. View

16.

Yellore V, Papp J, Sobel E, Khan M, Rayner S, Farber D . Replication and refinement of linkage of posterior polymorphous corneal dystrophy to the posterior polymorphous corneal dystrophy 1 locus on chromosome 20. Genet Med. 2007; 9(4):228-34. DOI: 10.1097/gim.0b013e31803c4dc2. View

17.

Toma N, Ebenezer N, Inglehearn C, Plant C, Ficker L, Bhattacharya S . Linkage of congenital hereditary endothelial dystrophy to chromosome 20. Hum Mol Genet. 1995; 4(12):2395-8. DOI: 10.1093/hmg/4.12.2395. View

18.

Cibis G, Krachmer J, Phelps C, Weingeist T . The clinical spectrum of posterior polymorphous dystrophy. Arch Ophthalmol. 1977; 95(9):1529-37. DOI: 10.1001/archopht.1977.04450090051002. View

19.

Guelman S, Kozuka K, Mao Y, Pham V, Solloway M, Wang J . The double-histone-acetyltransferase complex ATAC is essential for mammalian development. Mol Cell Biol. 2008; 29(5):1176-88. PMC: 2643826. DOI: 10.1128/MCB.01599-08. View

20.

Vandewalle C, VAN Roy F, Berx G . The role of the ZEB family of transcription factors in development and disease. Cell Mol Life Sci. 2008; 66(5):773-87. PMC: 11131515. DOI: 10.1007/s00018-008-8465-8. View