{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:38:39Z","timestamp":1790789919245,"version":"4.1.0"},"reference-count":64,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,4,3]],"date-time":"2020-04-03T00:00:00Z","timestamp":1585872000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,4,3]],"date-time":"2020-04-03T00:00:00Z","timestamp":1585872000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>As the primary indication for corneal transplantation, the pathogenesis of keratoconus remains elusive. Aiming to identify whether any mutation from extracellular-matrix (ECM)-related genes contributes to the patients with sporadic cases of keratoconus (KC) from Chinese Han population, one hundred and fifty-three participants in total were enrolled in our study, including fifty-three KC patients and one hundred healthy controls. Mutational analysis of three ECM-related genes (<jats:italic>LOX<\/jats:italic>, <jats:italic>COL5A1<\/jats:italic> and <jats:italic>TIMP3<\/jats:italic>) with next-generation sequencing and Sanger sequencing was performed. To further confirm the function of three ECM-related genes in the pathogenesis of keratoconus, we performed Real-time Quantitative PCR <jats:italic>in vitro<\/jats:italic>. Results showed that three new sequence variants (c.95\u2009G\u2009&gt;\u2009A in <jats:italic>LOX<\/jats:italic>, c.1372\u2009C\u2009&gt;\u2009T in <jats:italic>COL5A1<\/jats:italic> and c.476\u2009C\u2009&gt;\u2009T in <jats:italic>TIMP3<\/jats:italic>) were identified in aforementioned ECM-related genes in KC patients without being detected among the healthy controls. According to the results of QPCR, we found that the expression levels of <jats:italic>LOX<\/jats:italic> and <jats:italic>TIMP3<\/jats:italic> were decreased in the KC patients, while <jats:italic>COL5A1<\/jats:italic> showed no significant difference of expression. This is the first time to screen so many ECM-related genes in Chinese keratoconus patients using next-generation sequencing. We find numerous underlying causal variants, enlarging lots of mutation spectrums and thus providing new sites for other investigators to replicate and for further research.<\/jats:p>","DOI":"10.1038\/s41598-020-62572-0","type":"journal-article","created":{"date-parts":[[2020,4,3]],"date-time":"2020-04-03T10:06:32Z","timestamp":1585908392000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Three novel variants identified within ECM-related genes in Chinese Han keratoconus patients"],"prefix":"10.1038","volume":"10","author":[{"given":"Xiayan","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilei","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiyuan","family":"Ping","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoning","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuming","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8563-7419","authenticated-orcid":false,"given":"Xingchao","family":"Shentu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,4,3]]},"reference":[{"key":"62572_CR1","first-page":"296","volume":"23","author":"X Yu","year":"2017","unstructured":"Yu, X., Chen, B., Zhang, X. & Shentu, X. Identification of seven novel ZNF469 mutations in keratoconus patients in a Han Chinese population. Mol. Vis. 23, 296\u2013305 (2017).","journal-title":"Mol. Vis."},{"key":"62572_CR2","first-page":"795738","volume":"2015","author":"A Gordon-shaag","year":"2016","unstructured":"Gordon-shaag, A., Millodt, M., Shneor, E. & Liu, Y. The genetic and environmental factors for keratoconus. Biomed. Res. Int. 2015, 795738 (2016).","journal-title":"Biomed. Res. Int."},{"key":"62572_CR3","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1097\/ICO.0000000000000408","volume":"34","author":"JA Gomes","year":"2015","unstructured":"Gomes, J. A. et al. Global consensus on keratoconus and ectatic Diseases. Cornea 34, 359\u2013369 (2015).","journal-title":"Cornea"},{"key":"62572_CR4","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1097\/ICL.0000000000000085","volume":"40","author":"SE Brown","year":"2014","unstructured":"Brown, S. E., Simmasalam, R., Antonova, N., Gadaria, N. & Asbell, P. A. Progression in keratoconus and the effect of corneal cross-linking on progression. Eye Contact Lens 40, 331\u2013338 (2014).","journal-title":"Eye Contact Lens"},{"key":"62572_CR5","doi-asserted-by":"publisher","first-page":"7","DOI":"10.5005\/jp-journals-10025-1002","volume":"1","author":"A Gordon-Shaag","year":"2012","unstructured":"Gordon-Shaag, A., Millodot, M. & Shneor, E. The epidemiology and etiology of keratoconus. Int. J. Keratoconus Ectatic Corneal Dis. 1, 7\u201315 (2012).","journal-title":"Int. J. Keratoconus Ectatic Corneal Dis."},{"key":"62572_CR6","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1097\/ICO.0b013e3180de1e04","volume":"26","author":"V Kaya","year":"2007","unstructured":"Kaya, V. et al. Evaluation of the corneal topographic characteristics of keratoconus with orbscan II in patients with and without atopy. Cornea 26, 945\u2013948 (2007).","journal-title":"Cornea"},{"key":"62572_CR7","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1097\/ICO.0b013e3181cb410b","volume":"29","author":"AY Nemet","year":"2010","unstructured":"Nemet, A. Y., Vinker, S., Bahar, I. & Kaiserman, I. The association of keratoconus with immune disorders. Cornea 29, 1261\u20131264 (2010).","journal-title":"Cornea"},{"key":"62572_CR8","first-page":"3128","volume":"17","author":"S Saee-rad","year":"2011","unstructured":"Saee-rad, S. et al. Mutation analysis of VSX1 and SOD1 in Iranian patients with keratoconus. Mol. Vis. 17, 3128\u20133136 (2011).","journal-title":"Mol. Vis."},{"key":"62572_CR9","doi-asserted-by":"publisher","first-page":"746","DOI":"10.1097\/ICO.0b013e3181e16dd0","volume":"31","author":"JW Jeoung","year":"2012","unstructured":"Jeoung, J. W. et al. VSX1 gene and keratoconus: genetic analysis in Korean patients. Cornea 31, 746\u2013750 (2012).","journal-title":"Cornea"},{"key":"62572_CR10","doi-asserted-by":"publisher","first-page":"213","DOI":"10.3109\/13816810.2013.843712","volume":"36","author":"MM Moschos","year":"2015","unstructured":"Moschos, M. M. et al. Polymorphism analysis of VSX1 and SOD1 genes in Greek patients with keratoconus. Ophthalmic Genet. 36, 213\u2013217 (2015).","journal-title":"Ophthalmic Genet."},{"key":"62572_CR11","doi-asserted-by":"publisher","first-page":"3345","DOI":"10.1167\/iovs.05-1500","volume":"47","author":"N Udar","year":"2006","unstructured":"Udar, N. et al. SOD1: A candidate gene for keratoconus. Invest. Ophthalmol. Vis. Sci. 47, 3345\u20133351 (2006).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"62572_CR12","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.gene.2012.04.061","volume":"503","author":"T Guan","year":"2012","unstructured":"Guan, T., Liu, C., Ma, Z. & Ding, S. The point mutation and polymorphism in keratoconus candidate gene TGFBI in Chinese population. Gene 503, 137\u2013139 (2012).","journal-title":"Gene"},{"key":"62572_CR13","doi-asserted-by":"publisher","first-page":"604508","DOI":"10.1155\/2015\/604508","volume":"2015","author":"KK Abu-Amero","year":"2015","unstructured":"Abu-Amero, K. K. et al. Screening of the seed region of MIR184 in keratoconus patients from Saudi Arabia. Biomed. Res. Int. 2015, 604508 (2015).","journal-title":"Biomed. Res. Int."},{"key":"62572_CR14","doi-asserted-by":"publisher","first-page":"5266","DOI":"10.1167\/iovs.13-12035","volume":"54","author":"J Lechner","year":"2013","unstructured":"Lechner, J. et al. Mutational analysis of MIR184 in sporadic keratoconus and myopia. Invest. Ophthalmol. Vis. Sci. 54, 5266\u20135272 (2013).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"62572_CR15","doi-asserted-by":"publisher","first-page":"63","DOI":"10.5005\/jp-journals-10025-1123","volume":"5","author":"Y Bykhovskaya","year":"2016","unstructured":"Bykhovskaya, Y., Gromova, A., Makarenkova, H. P. & Rabinowitz, Y. S. Abnormal regulation of extracellular matrix and adhesion molecules in corneas of patients with keratoconus. Int. J. Keratoconus Ectatic Corneal Dis. 5, 63\u201370 (2016).","journal-title":"Int. J. Keratoconus Ectatic Corneal Dis."},{"key":"62572_CR16","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1046\/j.1442-9071.2001.d01-17.x","volume":"29","author":"SA Collier","year":"2001","unstructured":"Collier, S. A. Is the corneal degradation in keratoconus caused by matrix-metalloproteinases? Clin. Exp. Ophthalmol. 29, 340\u2013344 (2001).","journal-title":"Clin. Exp. Ophthalmol."},{"key":"62572_CR17","doi-asserted-by":"publisher","first-page":"6181","DOI":"10.1167\/iovs.10-70981","volume":"52","author":"M Mac\u00e9","year":"2011","unstructured":"Mac\u00e9, M. et al. Comparative transcriptome and network biology analyses demonstrate antiproliferative and hyperapoptotic phenotypes in human keratoconus corneas. Invest. Ophthalmol. Vis. Sci. 52, 6181\u20136191 (2011).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"62572_CR18","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1167\/iovs.04-1148","volume":"46","author":"YS Rabinowitz","year":"2005","unstructured":"Rabinowitz, Y. S., Dong, L. & Wistow, G. Gene expression profile studies of human keratoconus cornea for NEIBank: a novel cornea-expressed gene and the absence of transcripts for aquaporin 5. Invest. Ophthalmol. Vis. Sci. 46, 1239\u20131246 (2005).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"62572_CR19","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1097\/ICO.0b013e31818c9003","volume":"28","author":"TY Tai","year":"2009","unstructured":"Tai, T. Y. et al. Keratoconus associated with corneal stromal amyloid deposition containing TGFBIp. Cornea 28, 589\u2013593 (2009).","journal-title":"Cornea"},{"key":"62572_CR20","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1016\/0888-7543(91)90057-L","volume":"11","author":"ER H\u00e4m\u00e4l\u00e4inen","year":"1991","unstructured":"H\u00e4m\u00e4l\u00e4inen, E. R. et al. Molecular cloning of human lysyl oxidase and assignment of the gene to chromosome 5q23.3\u201331.2. Genomics 11, 508\u2013516 (1991).","journal-title":"Genomics"},{"key":"62572_CR21","doi-asserted-by":"crossref","first-page":"8666","DOI":"10.1016\/S0021-9258(18)42494-5","volume":"267","author":"PC Trackman","year":"1992","unstructured":"Trackman, P. C., Bedell-Hogan, D., Tang, J. & Kagan, H. M. Post-translational glycosylation and proteolytic processing of a lysyl oxidase precursor. J. Biol. Chem. 267, 8666\u20138671 (1992).","journal-title":"J. Biol. Chem."},{"key":"62572_CR22","doi-asserted-by":"publisher","first-page":"22537","DOI":"10.1074\/jbc.M102352200","volume":"276","author":"MI Uzel","year":"2001","unstructured":"Uzel, M. I. et al. Multiple bone morphogenetic protein 1-related mammalian metalloproteinases process pro-lysyl oxidase at the correct physiological site and control lysyl oxidase activation in mouse embryo fibroblast cultures. J. Biol. Chem. 276, 22537\u201322543 (2001).","journal-title":"J. Biol. Chem."},{"key":"62572_CR23","doi-asserted-by":"publisher","first-page":"C2095","DOI":"10.1152\/ajpcell.00613.2006","volume":"292","author":"Y Guo","year":"2007","unstructured":"Guo, Y., Pischon, N., Palamakumbura, A. H. & Trackman, P. C. Intracellular distribution of the lysyl oxidase propeptide in osteoblastic cells. Am. J. Physiol. Cell Physiol 292, C2095\u2013C2102 (2007).","journal-title":"Am. J. Physiol. Cell Physiol"},{"key":"62572_CR24","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1242\/jcs.95.4.649","volume":"95","author":"DE Birk","year":"1990","unstructured":"Birk, D. E., Fitch, J. M., Babiarz, J. P., Doane, K. J. & Linsenmayer, T. F. Collagen fibrillogenesis in vitro: interaction of types I and V collagen regulates fibril diameter. J. Cell Sci. 95, 649\u2013657 (1990).","journal-title":"J. Cell Sci."},{"key":"62572_CR25","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1083\/jcb.121.5.1181","volume":"121","author":"TF Linsenmayer","year":"1993","unstructured":"Linsenmayer, T. F. et al. Type V collagen: molecular structure and fibrillar organization of the chicken alpha 1(V) NH2-terminal domain, a putative regulator of corneal fibrillogenesis. J. Cell Biol. 121, 1181\u20131189 (1993).","journal-title":"J. Cell Biol."},{"key":"62572_CR26","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/S0968-4328(00)00043-3","volume":"32","author":"DE Birk","year":"2001","unstructured":"Birk, D. E. Type V collagen: heterotypic type I\/V collagen interactions in the regulation of fibril assembly. Micron 32, 223\u2013237 (2001).","journal-title":"Micron"},{"key":"62572_CR27","doi-asserted-by":"crossref","unstructured":"Birk, D. E. & Br\u00fcckner, P. Collagens, suprastructures, and collagen fibril assembly. The Extracellular Matrix: an Overview (2010).","DOI":"10.1007\/978-3-642-16555-9_3"},{"key":"62572_CR28","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1007\/s00441-006-0294-1","volume":"327","author":"M Roulet","year":"2007","unstructured":"Roulet, M., Ruggiero, F., Karsenty, G. & LeGuellec, D. A comprehensive study of the spatial and temporal expression of the col5a1 gene in mouse embryos: a clue for understanding collagen V function in developing connective tissues. Cell Tissue Res. 327, 323\u2013332 (2007).","journal-title":"Cell Tissue Res."},{"key":"62572_CR29","doi-asserted-by":"publisher","first-page":"4096","DOI":"10.1242\/jcs.091363","volume":"124","author":"M Sun","year":"2011","unstructured":"Sun, M. et al. Collagen V is a dominant regulator of collagen fibrillogenesis: dysfunctional regulation of structure and function in a corneal-stroma-specific Col5a1-null mouse model. J. Cell Sci. 124, 4096\u20134105 (2011).","journal-title":"J. Cell Sci."},{"key":"62572_CR30","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1167\/iovs.05-0771","volume":"47","author":"F Segev","year":"2006","unstructured":"Segev, F. et al. Structural abnormalities of the cornea and lid resulting from collagen V mutations. Invest. Ophthalmol. Vis. Sci. 47, 565\u2013573 (2006).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"62572_CR31","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/j.matbio.2015.03.005","volume":"44\u201346","author":"V Arpino","year":"2015","unstructured":"Arpino, V., Brock, M. & Gill, S. E. The role of TIMPs in regulation of extracellular matrix proteolysis. Matrix Biol. 44\u201346, 247\u2013254 (2015).","journal-title":"Matrix Biol."},{"key":"62572_CR32","first-page":"2480","volume":"15","author":"JE Lee","year":"2009","unstructured":"Lee, J. E., Oum, B. S., Choi, H. Y., Lee, S. U. & Lee, J. S. Evaluation of differentially expressed genes identified in keratoconus. Mol. Vis. 15, 2480\u20132487 (2009).","journal-title":"Mol. Vis."},{"key":"62572_CR33","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1016\/j.exer.2006.10.014","volume":"84","author":"S Hayes","year":"2007","unstructured":"Hayes, S., Boote, C., Tuft, S. J., Quantock, A. J. & Meek, K. M. A study of corneal thickness, shape and collagen organisation in keratoconus using videokeratography and X-ray scattering techniques. Exp. Eye Res. 84, 423\u2013434 (2007).","journal-title":"Exp. Eye Res."},{"key":"62572_CR34","doi-asserted-by":"publisher","first-page":"1948","DOI":"10.1167\/iovs.04-1253","volume":"46","author":"KM Meek","year":"2005","unstructured":"Meek, K. M. et al. Changes in collagen orientation and distribution in keratoconus corneas. Invest. Ophthalmol. Vis. Sci. 46, 1948\u20131956 (2005).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"62572_CR35","doi-asserted-by":"publisher","first-page":"e52860","DOI":"10.1371\/journal.pone.0052860","volume":"8","author":"S Hayes","year":"2013","unstructured":"Hayes, S. et al. The effect of riboflavin\/UVA collagen cross-linking therapy on the structure and hydrodynamic behaviour of the ungulate and rabbit corneal stroma. PLoS One 8, e52860 (2013).","journal-title":"PLoS One"},{"key":"62572_CR36","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1165\/ajrcmb\/5.3.206","volume":"5","author":"HM Kagan","year":"1991","unstructured":"Kagan, H. M. & Trackman, P. C. Properties and function of lysyl oxidase. Am. J. Respir. Cell Mol. Biol. 5, 206\u2013210 (1991).","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"62572_CR37","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.abb.2013.12.022","volume":"546","author":"J Finney","year":"2014","unstructured":"Finney, J., Moon, H. J., Ronnebaum, T., Lantz, M. & Mure, M. Human copper-dependent amine oxidases. Arch. Biochem. Biophys. 546, 19\u201332 (2014).","journal-title":"Arch. Biochem. Biophys."},{"key":"62572_CR38","first-page":"2482","volume":"17","author":"BP De","year":"2011","unstructured":"De, B. P. et al. Mutational screening of VSX1, SPARC, SOD1, LOX, and TIMP3 in keratoconus. Mol. Vis. 17, 2482\u20132494 (2011).","journal-title":"Mol. Vis."},{"key":"62572_CR39","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1007\/s00702-013-0993-1","volume":"120","author":"L Dudakova","year":"2013","unstructured":"Dudakova, L. & Jirsova, K. The impairment of lysyl oxidase in keratoconus and in keratoconus-associated disorders. J. Neural Transm. 120, 977\u2013982 (2013).","journal-title":"J. Neural Transm."},{"key":"62572_CR40","doi-asserted-by":"publisher","first-page":"309","DOI":"10.3109\/13816810.2014.881507","volume":"36","author":"F Hasanian-Langroudi","year":"2015","unstructured":"Hasanian-Langroudi, F., Saravani, R., Validad, M. H., Bahari, G. & Yari, D. Association of lysyl oxidase (LOX) polymorphisms with the risk of keratoconus in an Iranian population. Ophthalmic Genet. 36, 309\u2013314 (2015).","journal-title":"Ophthalmic Genet."},{"key":"62572_CR41","first-page":"12","volume":"21","author":"R Shetty","year":"2015","unstructured":"Shetty, R. et al. Attenuation of lysyl oxidase and collagen gene expression in keratoconus patient corneal epithelium corresponds to disease severity. Mol. Vis. 21, 12\u201325 (2015).","journal-title":"Mol. Vis."},{"key":"62572_CR42","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.exer.2012.09.005","volume":"104","author":"L Dudakova","year":"2012","unstructured":"Dudakova, L. et al. Changes in lysyl oxidase (LOX) distribution and its decreased activity in keratoconus corneas. Exp. Eye Res. 104, 74\u201381 (2012).","journal-title":"Exp. Eye Res."},{"key":"62572_CR43","doi-asserted-by":"publisher","first-page":"5372","DOI":"10.1167\/iovs.16-19677","volume":"57","author":"N Pahuja","year":"2016","unstructured":"Pahuja, N. et al. Differential molecular expression of extracellular matrix and iInflammatory genes at the corneal cone apex drives focal weakening in keratoconus. Invest. Opthalmol Vis. Sci. 57, 5372\u20135382 (2016).","journal-title":"Invest. Opthalmol Vis. Sci."},{"key":"62572_CR44","doi-asserted-by":"publisher","first-page":"8224","DOI":"10.1167\/iovs.13-12982","volume":"54","author":"S Sahebjada","year":"2013","unstructured":"Sahebjada, S. et al. Evaluating the association between keratoconus and the corneal thickness genes in an independent Australian population. Invest. Opthalmol Vis. Sci. 54, 8224\u20138228 (2013).","journal-title":"Invest. Opthalmol Vis. Sci."},{"key":"62572_CR45","doi-asserted-by":"publisher","first-page":"1581","DOI":"10.1038\/ejhg.2015.28","volume":"23","author":"L Dudakova","year":"2015","unstructured":"Dudakova, L. et al. Validation of rs2956540:G>C and rs3735520:G>A association with keratoconus in a population of European descent. Eur. J. Hum. Genet. 23, 1581\u20131583 (2015).","journal-title":"Eur. J. Hum. Genet."},{"key":"62572_CR46","doi-asserted-by":"publisher","first-page":"4152","DOI":"10.1167\/iovs.11-9268","volume":"53","author":"Y Bykhovskaya","year":"2012","unstructured":"Bykhovskaya, Y. et al. Variation in the lysyl Oxidase (LOX) gene is associated with keratoconus in family-based and case-control studies. Invest. Ophthalmol. Vis. Sci. 53, 4152\u20134157 (2012).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"62572_CR47","doi-asserted-by":"publisher","DOI":"10.1186\/s40662-016-0047-5","volume":"3","author":"Y Bykhovskaya","year":"2016","unstructured":"Bykhovskaya, Y., Margines, B. & Rabinowitz, Y. S. Genetics in keratoconus: where are we? Eye Vis. 3, 16 (2016).","journal-title":"Eye Vis."},{"key":"62572_CR48","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1038\/ng1297","volume":"36","author":"X Liu","year":"2004","unstructured":"Liu, X. et al. Elastic fiber homeostasis requires lysyl oxidase-like 1 protein. Nat. Genet. 36, 178\u2013182 (2004).","journal-title":"Nat. Genet."},{"key":"62572_CR49","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1007\/s12307-012-0105-z","volume":"5","author":"Q Xiao","year":"2012","unstructured":"Xiao, Q. & Ge, G. Lysyl oxidase, extracellular matrix remodeling and cancer metastasis. Cancer Microenviron. 5, 261\u2013273 (2012).","journal-title":"Cancer Microenviron."},{"key":"62572_CR50","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/j.jtos.2015.04.007","volume":"13","author":"C Mazzotta","year":"2015","unstructured":"Mazzotta, C. et al. In vivo confocal microscopy after corneal collagen cross-linking. Ocul. Surf. 13, 298\u2013314 (2015).","journal-title":"Ocul. Surf."},{"key":"62572_CR51","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1097\/ICO.0000000000001478","volume":"37","author":"R Shetty","year":"2017","unstructured":"Shetty, R. et al. Outcomes of corneal cross-linking correlate with cone-specific lysyl oxidase expression in patients with keratoconus. Cornea 37, 369\u2013374 (2017).","journal-title":"Cornea"},{"key":"62572_CR52","doi-asserted-by":"publisher","first-page":"2466","DOI":"10.1167\/iovs.02-0671","volume":"44","author":"K Nielsen","year":"2003","unstructured":"Nielsen, K., Birkenkamp-Demtr\u00f6der, K., Ehlers, N. & Orntoft, T. F. Identification of differentially expressed genes in keratoconus epithelium analyzed on microarrays. Invest. Opthalmol Vis. Sci. 44, 2466\u20132476 (2003).","journal-title":"Invest. Opthalmol Vis. Sci."},{"key":"62572_CR53","doi-asserted-by":"publisher","first-page":"2696","DOI":"10.1167\/iovs.13-11601","volume":"54","author":"X Li","year":"2013","unstructured":"Li, X. et al. Genetic association of COL5A1 variants in keratoconus patients suggests a complex connection between corneal thinning and keratoconus. Invest. Ophthalmol. Vis. Sci. 54, 2696\u20132704 (2013).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"62572_CR54","doi-asserted-by":"publisher","first-page":"4304","DOI":"10.1093\/hmg\/ddq349","volume":"19","author":"V Vitart","year":"2010","unstructured":"Vitart, V. et al. New loci associated with central cornea thickness include COL5A1, AKAP13 and AVGR8. Hum. Mol. Genet. 19, 4304\u20134311 (2010).","journal-title":"Hum. Mol. Genet."},{"key":"62572_CR55","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1093\/hmg\/ddq511","volume":"20","author":"EN Vithana","year":"2011","unstructured":"Vithana, E. N. et al. Collagen-related genes influence the glaucoma risk factor, central corneal thickness. Hum. Mol. Genet. 20, 649\u2013658 (2011).","journal-title":"Hum. Mol. Genet."},{"key":"62572_CR56","doi-asserted-by":"publisher","first-page":"e1000947","DOI":"10.1371\/journal.pgen.1000947","volume":"6","author":"Y Lu","year":"2010","unstructured":"Lu, Y. et al. Common genetic variants near the Brittle Cornea Syndrome locus ZNF469 Influence the blinding disease risk factor central corneal thickness. PLoS Genet. 6, e1000947 (2010).","journal-title":"PLoS Genet."},{"key":"62572_CR57","doi-asserted-by":"publisher","first-page":"1783","DOI":"10.1007\/s00439-012-1201-3","volume":"131","author":"R Hoehn","year":"2012","unstructured":"Hoehn, R. et al. Population-based meta-analysis in Caucasians confirms association with COL5A1 and ZNF469 but not COL8A2 with central corneal thickness. Hum. Genet. 131, 1783\u20131793 (2012).","journal-title":"Hum. Genet."},{"key":"62572_CR58","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1038\/ng.2506","volume":"45","author":"Y Lu","year":"2013","unstructured":"Lu, Y. et al. Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus. Nat. Genet. 45, 155\u2013163 (2013).","journal-title":"Nat. Genet."},{"key":"62572_CR59","doi-asserted-by":"publisher","first-page":"6049","DOI":"10.1128\/MCB.24.13.6049-6057.2004","volume":"24","author":"H Chanut-Delalande","year":"2004","unstructured":"Chanut-Delalande, H. et al. Development of a functional skin matrix requires deposition of collagen V heterotrimers. Mol. Cell Biol. 24, 6049\u20136057 (2004).","journal-title":"Mol. Cell Biol."},{"key":"62572_CR60","doi-asserted-by":"publisher","first-page":"12888","DOI":"10.1074\/jbc.M511528200","volume":"281","author":"RJ Wenstrup","year":"2006","unstructured":"Wenstrup, R. J. et al. Murine model of the Ehlers-Danlos syndrome: col5a1 haploinsufficiency disrupts collagen fibril assembly at multiple stages. J. Biol. Chem. 281, 12888\u201312895 (2006).","journal-title":"J. Biol. Chem."},{"key":"62572_CR61","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1002\/jcp.1041600122","volume":"160","author":"MD Johnson","year":"1994","unstructured":"Johnson, M. D. et al. Inhibition of angiogenesis by tissue inhibitor of metalloproteinase. J. Cell Physiol. 160, 194\u2013202 (1994).","journal-title":"J. Cell Physiol."},{"key":"62572_CR62","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1016\/j.exer.2007.02.013","volume":"84","author":"FJ Matthews","year":"2007","unstructured":"Matthews, F. J., Cook, S. D., Majid, M. A., Dick, A. D. & Smith, V. A. Changes in the balance of the tissue inhibitor of matrix metalloproteinases (TIMPs)-1 and -3 may promote keratocyte apoptosis in keratoconus. Exp. Eye Res. 84, 1125\u20131134 (2007).","journal-title":"Exp. Eye Res."},{"key":"62572_CR63","doi-asserted-by":"publisher","first-page":"5527","DOI":"10.1093\/hmg\/ddu253","volume":"23","author":"J Lechner","year":"2014","unstructured":"Lechner, J. et al. Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus. Hum. Mol. Genet. 23, 5527\u20135535 (2014).","journal-title":"Hum. Mol. Genet."},{"key":"62572_CR64","doi-asserted-by":"crossref","unstructured":"Shentu, X., Miao, Q., Tang, X., Yin, H. & Zhao, Y. Identification and functional analysis of a novel MIP gene mutation associated with congenital cataract in a Chinese family. Plos one 10, e0126679 (2015).","DOI":"10.1371\/journal.pone.0126679"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-62572-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-62572-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-62572-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T09:16:59Z","timestamp":1670318219000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-62572-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,3]]},"references-count":64,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["62572"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-62572-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,3]]},"assertion":[{"value":"16 April 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 March 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 April 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"5844"}}