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Published in: BMC Ophthalmology 1/2015

Open Access 01-12-2015 | Research article

Screening of potential target genes for cataract by analyzing mRNA expression profile of mouse Hsf4-null lens

Authors: Wenjuan Zhao, Wenqing Zhao, Jun Zhao, Dong Wang, Jinghai Li

Published in: BMC Ophthalmology | Issue 1/2015

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Abstract

Background

Hsf4 is closely related to the development of cataract. However, the molecular mechanisms remain unknown. This study aimed to explore the molecular mechanisms that how Hsf4 mutations influence development of lens and thus lead to cataract in mouse.

Methods

The mRNA expression profile of mouse tissue samples from Hsf4-null and wile-type lenses was downloaded from Gene Expression Omnibus database. Then the LIMMA package was used to screen differentially expressed genes (DEGs) and DAVID was applied to identify the significantly enriched Gene Ontology (GO) categories for DEGs. Furthermore, the protein-protein interaction (PPI) network of DEGs was constructed using Cytoscape and the key modules were selected from the PPI network based on the MCODE analysis.

Results

A total of 216 DEGs were screened, including 51 up- and 165 down-regulated genes. Meanwhile, nine GO terms were obtained, and DEGs such as SGK1, CRY2 and REV1 were enriched in response to DNA damage stimulus. Furthermore, 89 DEGs and 99 gene pairs were mapped into the PPI network and Ubc was the hob node. Two key modules, which contained the genes (e.g. Ubc, Egr1, Ptgs2, Hmox1, Cd44, Btg2, Cyr61 and Fos) were related to response to DNA damage stimulus.

Conclusions

The deletion of Hsf4 affects the expression of many genes, such as Ubc, Ptgs2, Egr1 and Fos. These genes may be involved in the development of cataract and could be used as therapeutic targets for cataract.
Literature
1.
3.
go back to reference Courtney P. The National Cataract Surgery Survey: I. Method and descriptive features. Eye. 1992;6:487–92.CrossRefPubMed Courtney P. The National Cataract Surgery Survey: I. Method and descriptive features. Eye. 1992;6:487–92.CrossRefPubMed
4.
go back to reference Qureshi N, Ahmed T, Ahmed T. Opacities in optical media to cause diminished vision. Pak J Surg. 2014;30:63–6. Qureshi N, Ahmed T, Ahmed T. Opacities in optical media to cause diminished vision. Pak J Surg. 2014;30:63–6.
5.
go back to reference Cui X, Wang L, Zhang J, Du R, Liao S, Li D, et al. HSF4 regulates DLAD expression and promotes lens de-nucleation. Biochim Biophys Acta. 1832;2013:1167–72. Cui X, Wang L, Zhang J, Du R, Liao S, Li D, et al. HSF4 regulates DLAD expression and promotes lens de-nucleation. Biochim Biophys Acta. 1832;2013:1167–72.
6.
go back to reference Fujimoto M, Izu H, Seki K, Fukuda K, Nishida T, Yamada S, et al. HSF4 is required for normal cell growth and differentiation during mouse lens development. EMBO J. 2004;23:4297–306.CrossRefPubMedPubMedCentral Fujimoto M, Izu H, Seki K, Fukuda K, Nishida T, Yamada S, et al. HSF4 is required for normal cell growth and differentiation during mouse lens development. EMBO J. 2004;23:4297–306.CrossRefPubMedPubMedCentral
7.
go back to reference Nakai A, Tanabe M, Kawazoe Y, Inazawa J, Morimoto RI, Nagata K. HSF4, a new member of the human heat shock factor family which lacks properties of a transcriptional activator. Mol Cell Biol. 1997;17:469–81.CrossRefPubMedPubMedCentral Nakai A, Tanabe M, Kawazoe Y, Inazawa J, Morimoto RI, Nagata K. HSF4, a new member of the human heat shock factor family which lacks properties of a transcriptional activator. Mol Cell Biol. 1997;17:469–81.CrossRefPubMedPubMedCentral
8.
go back to reference Cui X, Zhang J, Du R, Wang L, Archacki S, Zhang Y, et al. HSF4 is involved in DNA damage repair through regulation of Rad51. Biochim Biophys Acta. 1822;2012:1308–15. Cui X, Zhang J, Du R, Wang L, Archacki S, Zhang Y, et al. HSF4 is involved in DNA damage repair through regulation of Rad51. Biochim Biophys Acta. 1822;2012:1308–15.
9.
go back to reference Shi Y, Shi X, Jin Y, Miao A, Bu L, He J, et al. Mutation screening of HSF4 in 150 age-related cataract patients. Mol Vis. 2008;14:1850–5.PubMedPubMedCentral Shi Y, Shi X, Jin Y, Miao A, Bu L, He J, et al. Mutation screening of HSF4 in 150 age-related cataract patients. Mol Vis. 2008;14:1850–5.PubMedPubMedCentral
10.
go back to reference Bu L, Jin Y, Shi Y, Chu R, Ban A, Eiberg H, et al. Mutant DNA-binding domain of HSF4 is associated with autosomal dominant lamellar and Marner cataract. Nat Genet. 2002;31:276–8.CrossRefPubMed Bu L, Jin Y, Shi Y, Chu R, Ban A, Eiberg H, et al. Mutant DNA-binding domain of HSF4 is associated with autosomal dominant lamellar and Marner cataract. Nat Genet. 2002;31:276–8.CrossRefPubMed
11.
go back to reference Ke T, Wang QK, Ji B, Wang X, Liu P, Zhang X, et al. Novel HSF4 mutation causes congenital total white cataract in a Chinese family. Am J Ophthalmol. 2006;142:298–303.CrossRefPubMed Ke T, Wang QK, Ji B, Wang X, Liu P, Zhang X, et al. Novel HSF4 mutation causes congenital total white cataract in a Chinese family. Am J Ophthalmol. 2006;142:298–303.CrossRefPubMed
12.
go back to reference Smaoui N, Beltaief O, BenHamed S, M’Rad R, Maazoul F, Ouertani A, et al. A homozygous splice mutation in the HSF4 gene is associated with an autosomal recessive congenital cataract. Invest Ophthalmol Vis Sci. 2004;45:2716–21.CrossRefPubMed Smaoui N, Beltaief O, BenHamed S, M’Rad R, Maazoul F, Ouertani A, et al. A homozygous splice mutation in the HSF4 gene is associated with an autosomal recessive congenital cataract. Invest Ophthalmol Vis Sci. 2004;45:2716–21.CrossRefPubMed
13.
go back to reference Forshew T, Johnson CA, Khaliq S, Pasha S, Willis C, Abbasi R, et al. Locus heterogeneity in autosomal recessive congenital cataracts: linkage to 9q and germline HSF4 mutations. Hum Genet. 2005;117:452–9.CrossRefPubMed Forshew T, Johnson CA, Khaliq S, Pasha S, Willis C, Abbasi R, et al. Locus heterogeneity in autosomal recessive congenital cataracts: linkage to 9q and germline HSF4 mutations. Hum Genet. 2005;117:452–9.CrossRefPubMed
14.
go back to reference Sajjad N, Goebel I, Kakar N, Cheema AM, Kubisch C, Ahmad J. A novel HSF4 gene mutation (p.R405X) causing autosomal recessive congenital cataracts in a large consanguineous family from Pakistan. BMC Med Genet. 2008;9:1471–2350.CrossRef Sajjad N, Goebel I, Kakar N, Cheema AM, Kubisch C, Ahmad J. A novel HSF4 gene mutation (p.R405X) causing autosomal recessive congenital cataracts in a large consanguineous family from Pakistan. BMC Med Genet. 2008;9:1471–2350.CrossRef
15.
go back to reference Shi X, Cui B, Wang Z, Weng L, Xu Z, Ma J, et al. Removal of Hsf4 leads to cataract development in mice through down-regulation of γS-crystallin and Bfsp expression. BMC Mol Biol. 2009;10:10.CrossRefPubMedPubMedCentral Shi X, Cui B, Wang Z, Weng L, Xu Z, Ma J, et al. Removal of Hsf4 leads to cataract development in mice through down-regulation of γS-crystallin and Bfsp expression. BMC Mol Biol. 2009;10:10.CrossRefPubMedPubMedCentral
17.
go back to reference Ueda M, Ota J, Yamashita Y, Choi YL, Ohki R, Wada T, et al. DNA microarray analysis of stage progression mechanism in myelodysplastic syndrome. Br J Haematol. 2003;123:288–96.CrossRefPubMed Ueda M, Ota J, Yamashita Y, Choi YL, Ohki R, Wada T, et al. DNA microarray analysis of stage progression mechanism in myelodysplastic syndrome. Br J Haematol. 2003;123:288–96.CrossRefPubMed
18.
go back to reference He S, Pirity MK, Wang W-L, Wolf L, Chauhan BK, Cveklova K, et al. Chromatin remodeling enzyme Brg1 is required for mouse lens fiber cell terminal differentiation and its denucleation. Epigenetics Chromatin. 2010;3:21.CrossRefPubMedPubMedCentral He S, Pirity MK, Wang W-L, Wolf L, Chauhan BK, Cveklova K, et al. Chromatin remodeling enzyme Brg1 is required for mouse lens fiber cell terminal differentiation and its denucleation. Epigenetics Chromatin. 2010;3:21.CrossRefPubMedPubMedCentral
19.
go back to reference Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, et al. NCBI GEO: archive for functional genomics data sets—update. Nucleic Acids Res. 2013;41:D991–D5.CrossRefPubMed Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, et al. NCBI GEO: archive for functional genomics data sets—update. Nucleic Acids Res. 2013;41:D991–D5.CrossRefPubMed
20.
go back to reference Gautier L, Cope L, Bolstad BM, Irizarry RA. affy—analysis of Affymetrix GeneChip data at the probe level. Bioinformatics. 2004;20:307–15.CrossRefPubMed Gautier L, Cope L, Bolstad BM, Irizarry RA. affy—analysis of Affymetrix GeneChip data at the probe level. Bioinformatics. 2004;20:307–15.CrossRefPubMed
21.
go back to reference Smyth GK. Limma: linear models for microarray data. Bioinformatics and computational biology solutions using R and Bioconductor. New York: Springer; 2005. p. 397–420.CrossRef Smyth GK. Limma: linear models for microarray data. Bioinformatics and computational biology solutions using R and Bioconductor. New York: Springer; 2005. p. 397–420.CrossRef
22.
go back to reference Benjamini Y. Discovering the false discovery rate. J Roy Stat Soc B. 2010;72:405–16.CrossRef Benjamini Y. Discovering the false discovery rate. J Roy Stat Soc B. 2010;72:405–16.CrossRef
23.
go back to reference Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc B. 1995;57:289–300. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc B. 1995;57:289–300.
24.
go back to reference Wang L, Cao C, Ma Q, Zeng Q, Wang H, Cheng Z, et al. RNA-seq analyses of multiple meristems of soybean: novel and alternative transcripts, evolutionary and functional implications. BMC Plant Biol. 2014;14:169.CrossRefPubMedPubMedCentral Wang L, Cao C, Ma Q, Zeng Q, Wang H, Cheng Z, et al. RNA-seq analyses of multiple meristems of soybean: novel and alternative transcripts, evolutionary and functional implications. BMC Plant Biol. 2014;14:169.CrossRefPubMedPubMedCentral
25.
go back to reference da Huang W, Sherman BT, Tan Q, Collins JR, Alvord WG, Roayaei J, et al. The DAVID Gene Functional Classification Tool: a novel biological module-centric algorithm to functionally analyze large gene lists. Genome Biol. 2007;8:R183.CrossRefPubMedPubMedCentral da Huang W, Sherman BT, Tan Q, Collins JR, Alvord WG, Roayaei J, et al. The DAVID Gene Functional Classification Tool: a novel biological module-centric algorithm to functionally analyze large gene lists. Genome Biol. 2007;8:R183.CrossRefPubMedPubMedCentral
26.
go back to reference Von Mering C, Huynen M, Jaeggi D, Schmidt S, Bork P, Snel B. STRING: a database of predicted functional associations between proteins. Nucleic Acids Res. 2003;31:258–61.CrossRef Von Mering C, Huynen M, Jaeggi D, Schmidt S, Bork P, Snel B. STRING: a database of predicted functional associations between proteins. Nucleic Acids Res. 2003;31:258–61.CrossRef
27.
go back to reference Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A, et al. STRING v9. 1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res. 2013;41:D808–D15.CrossRefPubMed Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A, et al. STRING v9. 1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res. 2013;41:D808–D15.CrossRefPubMed
28.
go back to reference Smoot ME, Ono K, Ruscheinski J, Wang PL, Ideker T. Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics. 2011;27:431–2.CrossRefPubMed Smoot ME, Ono K, Ruscheinski J, Wang PL, Ideker T. Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics. 2011;27:431–2.CrossRefPubMed
29.
30.
31.
go back to reference Enoki Y, Mukoda Y, Furutani C, Sakurai H. DNA-binding and transcriptional activities of human HSF4 containing mutations that associate with congenital and age-related cataracts. Biochim Biophys Acta. 2010;1802:749–53.CrossRefPubMed Enoki Y, Mukoda Y, Furutani C, Sakurai H. DNA-binding and transcriptional activities of human HSF4 containing mutations that associate with congenital and age-related cataracts. Biochim Biophys Acta. 2010;1802:749–53.CrossRefPubMed
32.
go back to reference Lv H, Huang C, Zhang J, Liu Z, Zhang Z, Xu H, et al. A Novel HSF4 Gene Mutation Causes Autosomal-Dominant Cataracts in a Chinese Family. G3 (Bethesda). 2014;4:823–8.CrossRef Lv H, Huang C, Zhang J, Liu Z, Zhang Z, Xu H, et al. A Novel HSF4 Gene Mutation Causes Autosomal-Dominant Cataracts in a Chinese Family. G3 (Bethesda). 2014;4:823–8.CrossRef
33.
go back to reference Øsnes-Ringen O, Azqueta AO, Moe MC, Zetterström C, Røger M, Nicolaissen B, et al. DNA damage in lens epithelium of cataract patients in vivo and ex vivo. Acta Ophthalmol. 2013;91:652–6.CrossRefPubMed Øsnes-Ringen O, Azqueta AO, Moe MC, Zetterström C, Røger M, Nicolaissen B, et al. DNA damage in lens epithelium of cataract patients in vivo and ex vivo. Acta Ophthalmol. 2013;91:652–6.CrossRefPubMed
34.
go back to reference Kleiman NJ, Spector A. DNA single strand breaks in human lens epithelial cells from patients with cataract. Curr Eye Res. 1993;12:423–31.CrossRefPubMed Kleiman NJ, Spector A. DNA single strand breaks in human lens epithelial cells from patients with cataract. Curr Eye Res. 1993;12:423–31.CrossRefPubMed
35.
go back to reference Sorte K, Sune P, Bhake A, Shivkumar V, Gangane N, Basak A. Quantitative assessment of DNA damage directly in lens epithelial cells from senile cataract patients. Mol Vis. 2011;17:1.PubMedPubMedCentral Sorte K, Sune P, Bhake A, Shivkumar V, Gangane N, Basak A. Quantitative assessment of DNA damage directly in lens epithelial cells from senile cataract patients. Mol Vis. 2011;17:1.PubMedPubMedCentral
36.
go back to reference Zhang J, Wu J, Yang L, Zhu R, Yang M, Qin B, et al. DNA damage in lens epithelial cells and peripheral lymphocytes from age-related cataract patients. Ophthalmic Res. 2013;51:124–8.CrossRef Zhang J, Wu J, Yang L, Zhu R, Yang M, Qin B, et al. DNA damage in lens epithelial cells and peripheral lymphocytes from age-related cataract patients. Ophthalmic Res. 2013;51:124–8.CrossRef
37.
go back to reference Liegel RP, Handley MT, Ronchetti A, Brown S, Langemeyer L, Linford A, et al. Loss-of-function mutations in TBC1D20 cause cataracts and male infertility in blind sterile mice and Warburg micro syndrome in humans. Am J Hum Genet. 2013;93:1001–14.CrossRefPubMedPubMedCentral Liegel RP, Handley MT, Ronchetti A, Brown S, Langemeyer L, Linford A, et al. Loss-of-function mutations in TBC1D20 cause cataracts and male infertility in blind sterile mice and Warburg micro syndrome in humans. Am J Hum Genet. 2013;93:1001–14.CrossRefPubMedPubMedCentral
38.
40.
go back to reference Ryu KY, Maehr R, Gilchrist CA, Long MA, Bouley DM, Mueller B, et al. The mouse polyubiquitin gene UbC is essential for fetal liver development, cell-cycle progression and stress tolerance. EMBO J. 2007;26:2693–706.CrossRefPubMedPubMedCentral Ryu KY, Maehr R, Gilchrist CA, Long MA, Bouley DM, Mueller B, et al. The mouse polyubiquitin gene UbC is essential for fetal liver development, cell-cycle progression and stress tolerance. EMBO J. 2007;26:2693–706.CrossRefPubMedPubMedCentral
41.
go back to reference Jahngen-Hodge J, Cyr D, Laxman E, Taylor A. Ubiquitin and ubiquitin conjugates in human lens. Exp Eye Res. 1992;55:897–902.CrossRefPubMed Jahngen-Hodge J, Cyr D, Laxman E, Taylor A. Ubiquitin and ubiquitin conjugates in human lens. Exp Eye Res. 1992;55:897–902.CrossRefPubMed
42.
go back to reference Morishita H, Eguchi S, Kimura H, Sasaki J, Sakamaki Y, Robinson ML, et al. Deletion of autophagy-related 5 (Atg5) and Pik3c3 genes in the lens causes cataract independent of programmed organelle degradation. J Biol Chem. 2013;288:11436–47.CrossRefPubMedPubMedCentral Morishita H, Eguchi S, Kimura H, Sasaki J, Sakamaki Y, Robinson ML, et al. Deletion of autophagy-related 5 (Atg5) and Pik3c3 genes in the lens causes cataract independent of programmed organelle degradation. J Biol Chem. 2013;288:11436–47.CrossRefPubMedPubMedCentral
43.
go back to reference Kimura Y, Tanaka K. Regulatory mechanisms involved in the control of ubiquitin homeostasis. J Biochem. 2010;147:793–8.CrossRefPubMed Kimura Y, Tanaka K. Regulatory mechanisms involved in the control of ubiquitin homeostasis. J Biochem. 2010;147:793–8.CrossRefPubMed
44.
go back to reference Imai F, Yoshizawa A, Fujimori-Tonou N, Kawakami K, Masai I. The ubiquitin proteasome system is required for cell proliferation of the lens epithelium and for differentiation of lens fiber cells in zebrafish. Development. 2010;137:3257–68.CrossRefPubMed Imai F, Yoshizawa A, Fujimori-Tonou N, Kawakami K, Masai I. The ubiquitin proteasome system is required for cell proliferation of the lens epithelium and for differentiation of lens fiber cells in zebrafish. Development. 2010;137:3257–68.CrossRefPubMed
45.
go back to reference Liou J-Y, Deng W-G, Gilroy DW, Shyue S-K, Wu KK. Colocalization and interaction of cyclooxygenase-2 with caveolin-1 in human fibroblasts. J Biol Chem. 2001;276:34975–82.CrossRefPubMed Liou J-Y, Deng W-G, Gilroy DW, Shyue S-K, Wu KK. Colocalization and interaction of cyclooxygenase-2 with caveolin-1 in human fibroblasts. J Biol Chem. 2001;276:34975–82.CrossRefPubMed
46.
go back to reference Lo W-K, C-j Z, Reddan J. Identification of caveolae and their signature proteins caveolin 1 and 2 in the lens. Exp Eye Res. 2004;79:487–98.CrossRefPubMed Lo W-K, C-j Z, Reddan J. Identification of caveolae and their signature proteins caveolin 1 and 2 in the lens. Exp Eye Res. 2004;79:487–98.CrossRefPubMed
47.
go back to reference Zhu H, Yue J, Pan Z, Wu H, Cheng Y, Lu H, et al. Involvement of Caveolin-1 in repair of DNA damage through both homologous recombination and non-homologous end joining. PLoS One. 2010;5:e12055.CrossRefPubMedPubMedCentral Zhu H, Yue J, Pan Z, Wu H, Cheng Y, Lu H, et al. Involvement of Caveolin-1 in repair of DNA damage through both homologous recombination and non-homologous end joining. PLoS One. 2010;5:e12055.CrossRefPubMedPubMedCentral
48.
go back to reference Rhim JH, Kim JH, Yeo E-J, Kim JC, Park SC. Caveolin-1 as a novel indicator of wound-healing capacity in aged human corneal epithelium. Mol Med. 2010;16:527.CrossRefPubMedPubMedCentral Rhim JH, Kim JH, Yeo E-J, Kim JC, Park SC. Caveolin-1 as a novel indicator of wound-healing capacity in aged human corneal epithelium. Mol Med. 2010;16:527.CrossRefPubMedPubMedCentral
49.
go back to reference Ashby RS, Zeng G, Leotta AJ, Dennis YT, McFadden SA. Egr-1 mRNA Expression Is a Marker for the Direction of Mammalian Ocular Growth. Invest Ophthalmol Vis Sci. 2014;55:5911–21.CrossRefPubMed Ashby RS, Zeng G, Leotta AJ, Dennis YT, McFadden SA. Egr-1 mRNA Expression Is a Marker for the Direction of Mammalian Ocular Growth. Invest Ophthalmol Vis Sci. 2014;55:5911–21.CrossRefPubMed
50.
go back to reference Abate C, Luk D, Gagne E, Roeder RG, Curran T. Fos and jun cooperate in transcriptional regulation via heterologous activation domains. Mol Cell Biol. 1990;10:5532–5.CrossRefPubMedPubMedCentral Abate C, Luk D, Gagne E, Roeder RG, Curran T. Fos and jun cooperate in transcriptional regulation via heterologous activation domains. Mol Cell Biol. 1990;10:5532–5.CrossRefPubMedPubMedCentral
51.
go back to reference Mahner S, Baasch C, Schwarz J, Hein S, Wolber L, Janicke F, et al. C-Fos expression is a molecular predictor of progression and survival in epithelial ovarian carcinoma. Br J Cancer. 2008;99:1269–75.CrossRefPubMedPubMedCentral Mahner S, Baasch C, Schwarz J, Hein S, Wolber L, Janicke F, et al. C-Fos expression is a molecular predictor of progression and survival in epithelial ovarian carcinoma. Br J Cancer. 2008;99:1269–75.CrossRefPubMedPubMedCentral
52.
go back to reference Bossis G, Malnou CE, Farras R, Andermarcher E, Hipskind R, Rodriguez M, et al. Down-regulation of c-Fos/c-Jun AP-1 dimer activity by sumoylation. Mol Cell Biol. 2005;25:6964–79.CrossRefPubMedPubMedCentral Bossis G, Malnou CE, Farras R, Andermarcher E, Hipskind R, Rodriguez M, et al. Down-regulation of c-Fos/c-Jun AP-1 dimer activity by sumoylation. Mol Cell Biol. 2005;25:6964–79.CrossRefPubMedPubMedCentral
53.
go back to reference Rinaudo JAS, Zelenka PS. Expression of c-fos and c-jun mRNA in the developing chicken lens: relationship to cell proliferation, quiescence, and differentiation. Exp Cell Res. 1992;199:147–53.CrossRefPubMed Rinaudo JAS, Zelenka PS. Expression of c-fos and c-jun mRNA in the developing chicken lens: relationship to cell proliferation, quiescence, and differentiation. Exp Cell Res. 1992;199:147–53.CrossRefPubMed
Metadata
Title
Screening of potential target genes for cataract by analyzing mRNA expression profile of mouse Hsf4-null lens
Authors
Wenjuan Zhao
Wenqing Zhao
Jun Zhao
Dong Wang
Jinghai Li
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Ophthalmology / Issue 1/2015
Electronic ISSN: 1471-2415
DOI
https://doi.org/10.1186/s12886-015-0066-3

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