{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:00:22Z","timestamp":1791896422781,"version":"4.3.4"},"reference-count":55,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,22]],"date-time":"2021-02-22T00:00:00Z","timestamp":1613952000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["205174\/Z\/16\/Z"],"award-info":[{"award-number":["205174\/Z\/16\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012618","name":"National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology","doi-asserted-by":"publisher","award":["\/"],"award-info":[{"award-number":["\/"]}],"id":[{"id":"10.13039\/501100012618","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017645","name":"Moorfields Eye Charity","doi-asserted-by":"publisher","award":["\/"],"award-info":[{"award-number":["\/"]}],"id":[{"id":"10.13039\/501100017645","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Leadiant Biosciences","award":["\/"],"award-info":[{"award-number":["\/"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>EPHA2 is a transmembrane tyrosine kinase receptor that, when disrupted, causes congenital and age-related cataracts. Cat-Map reports 22 pathogenic EPHA2 variants associated with congenital cataracts, variable microcornea, and lenticonus, but no previous association with microphthalmia (small, underdeveloped eye, \u22652 standard deviations below normal axial length). Microphthalmia arises from ocular maldevelopment with &gt;90 monogenic causes, and can include a complex ocular phenotype. In this paper, we report two pathogenic EPHA2 variants in unrelated families presenting with bilateral microphthalmia and congenital cataracts. Whole genome sequencing through the 100,000 Genomes Project and cataract-related targeted gene panel testing identified autosomal dominant heterozygous mutations segregating with the disease: (i) missense c.1751C&gt;T, p.(Pro584Leu) and (ii) splice site c.2826-9G&gt;A. To functionally validate pathogenicity, morpholino knockdown of epha2a\/epha2b in zebrafish resulted in significantly reduced eye size \u00b1 cataract formation. Misexpression of N-cadherin and retained fibre cell nuclei were observed in the developing lens of the epha2b knockdown morphant fish by 3 days post-fertilisation, which indicated a putative mechanism for microphthalmia pathogenesis through disruption of cadherin-mediated adherens junctions, preventing lens maturation and the critical signals stimulating eye growth. This study demonstrates a novel association of EPHA2 with microphthalmia, suggesting further analysis of pathogenic variants in unsolved microphthalmia cohorts may increase molecular diagnostic rates.<\/jats:p>","DOI":"10.3390\/ijms22042190","type":"journal-article","created":{"date-parts":[[2021,2,22]],"date-time":"2021-02-22T20:42:51Z","timestamp":1614026571000},"page":"2190","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["EPHA2 Segregates with Microphthalmia and Congenital Cataracts in Two Unrelated Families"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0763-3516","authenticated-orcid":false,"given":"Philippa","family":"Harding","sequence":"first","affiliation":[{"name":"Institute of Ophthalmology, University College London, London EC1V 9EL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Toms","sequence":"additional","affiliation":[{"name":"Institute of Ophthalmology, University College London, London EC1V 9EL, UK"},{"name":"The Francis Crick Institute, London NW1 1AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9848-1302","authenticated-orcid":false,"given":"Elena","family":"Schiff","sequence":"additional","affiliation":[{"name":"Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5598-6274","authenticated-orcid":false,"given":"Nicholas","family":"Owen","sequence":"additional","affiliation":[{"name":"Institute of Ophthalmology, University College London, London EC1V 9EL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3328-3698","authenticated-orcid":false,"given":"Suzannah","family":"Bell","sequence":"additional","affiliation":[{"name":"Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6460-3415","authenticated-orcid":false,"given":"Ian Christopher","family":"Lloyd","sequence":"additional","affiliation":[{"name":"Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK"},{"name":"Manchester Academic Health Sciences Centre, University of Manchester, Manchester, M13 9PT, UK"},{"name":"Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1688-5360","authenticated-orcid":false,"given":"Mariya","family":"Moosajee","sequence":"additional","affiliation":[{"name":"Institute of Ophthalmology, University College London, London EC1V 9EL, UK"},{"name":"The Francis Crick Institute, London NW1 1AT, UK"},{"name":"Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK"},{"name":"Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,22]]},"reference":[{"key":"ref_1","first-page":"2042","article-title":"The EPHA2 gene is associated with cataracts linked to 1p","volume":"14","author":"Shiels","year":"2008","journal-title":"Mol. Vis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/j.biocel.2008.07.019","article-title":"Eph\/ephrin signaling in epithelial development and homeostasis","volume":"41","author":"Miao","year":"2009","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_3","first-page":"254","article-title":"Further analysis of the lens of ephrin-A5\u2212\/\u2212mice: Development of postnatal defects","volume":"19","author":"Son","year":"2013","journal-title":"Mol. Vis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"E603","DOI":"10.1002\/humu.20995","article-title":"Mutations of the EPHA2 receptor tyrosine kinase gene cause autosomal dominant congenital cataract","volume":"30","author":"Zhang","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Dave, A., Laurie, K., Staffieri, S.E., Taranath, D., Mackey, D.A., Mitchell, P., Wang, J.J., Craig, J.E., Burdon, K.P., and Sharma, S. (2013). Mutations in the EPHA2 Gene Are a Major Contributor to Inherited Cataracts in South-Eastern Australia. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0072518"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"334","DOI":"10.3390\/genes4030334","article-title":"Roles of EphA2 in development and disease","volume":"4","author":"Park","year":"2013","journal-title":"Genes"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.diff.2018.05.002","article-title":"Epha2 and Efna5 participate in lens cell pattern-formation","volume":"102","author":"Zhou","year":"2018","journal-title":"Differentiation"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"F855","DOI":"10.1152\/ajprenal.00347.2004","article-title":"EphA2: Expression in the renal medulla and regulation by hypertonicity and urea stress in vitro and in vivo","volume":"288","author":"Xu","year":"2005","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1002\/dvdy.22632","article-title":"Ephrin\/ephrin receptor expression during early stages of mouse inner ear development","volume":"240","author":"Saeger","year":"2011","journal-title":"Dev. Dyn."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"16620","DOI":"10.1073\/pnas.0808987105","article-title":"Loss of ephrin-A5 function disrupts lens fiber cell packing and leads to cataract","volume":"105","author":"Cooper","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","first-page":"2937","article-title":"The status of intercellular junctions in established lens epithelial cell lines","volume":"18","author":"Dave","year":"2012","journal-title":"Mol. Vis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.ydbio.2008.10.011","article-title":"Co-operative roles for E-cadherin and N-cadherin during lens vesicle separation and lens epithelial cell survival","volume":"326","author":"Pontoriero","year":"2009","journal-title":"Dev. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Jun, G., Guo, H., Klein, B.E.K., Klein, R., Wang, J.J., Mitchell, P., Miao, H., Lee, K.E., Joshi, T., and Buck, M. (2009). EPHA2 Is Associated with Age-Related Cortical Cataract in Mice and Humans. PLoS Genet., 5.","DOI":"10.1371\/journal.pgen.1000584"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"263300402093806","DOI":"10.1177\/2633004020938061","article-title":"Congenital cataract: A guide to genetic and clinical management","volume":"1","author":"Bell","year":"2020","journal-title":"Ther. Adv. Rare Dis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Lin, H., Yang, Y., Chen, J., Zhong, X., Liu, Z., Lin, Z., Chen, W., Luo, L., Qu, B., and Zhang, X. (2014). Congenital Cataract: Prevalence and Surgery Age at Zhongshan Ophthalmic Center (ZOC). PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0101781"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"107872","DOI":"10.1016\/j.exer.2019.107872","article-title":"Molecular genetics of congenital cataracts","volume":"191","author":"Li","year":"2020","journal-title":"Exp. Eye Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"274","DOI":"10.3109\/14767058.2016.1169526","article-title":"Fetal and neonatal abnormalities due to congenital rubella syndrome: A review of literature","volume":"30","author":"Yazigi","year":"2017","journal-title":"J. Matern. Neonatal Med."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Bell, S., Malka, S., Lloyd, I.C., and Moosajee, M. (2021). Clinical Spectrum and Genetic Diagnosis of 54 Consecutive Patients Aged 0\u201325 with Bilateral Cataracts. Genes, 12.","DOI":"10.3390\/genes12020131"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/1750-1172-2-47","article-title":"Anophthalmia and microphthalmia","volume":"2","author":"Verma","year":"2007","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/s12276-018-0079-0","article-title":"Mutation of IPO13 causes recessive ocular coloboma, microphthalmia, and cataract","volume":"50","author":"Huang","year":"2018","journal-title":"Exp. Mol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1007\/s00439-018-1875-2","article-title":"New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies","volume":"138","author":"Ceroni","year":"2019","journal-title":"Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Marakhonov, A.V., Voskresenskaya, A.A., Ballesta, M.J., Konovalov, F.A., Vasilyeva, T.A., Blanco-Kelly, F., Pozdeyeva, N.A., Kadyshev, V.V., L\u00f3pez-Gonz\u00e1lez, V., and Guillen, E. (2020). Expanding the phenotype of CRYAA nucleotide variants to a complex presentation of anterior segment dysgenesis. Orphanet J. Rare Dis., 15.","DOI":"10.1186\/s13023-020-01484-8"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5789","DOI":"10.1093\/hmg\/ddv298","article-title":"Mutations in SIPA1L3 cause eye defects through disruption of cell polarity and cytoskeleton organization","volume":"24","author":"Greenlees","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1038\/sj.ejhg.5201671","article-title":"New mutations in the NHS gene in Nance-Horan Syndrome families from the Netherlands","volume":"14","author":"Florijn","year":"2006","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1080\/02713683.2019.1675176","article-title":"A novel mutation p.S93R in CRYBB1 associated with dominant congenital cataract and microphthalmia","volume":"45","author":"Jin","year":"2019","journal-title":"Curr. Eye Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/78071","article-title":"Human microphthalmia associated with mutations in the retinal homeobox gene CHX10","volume":"25","author":"Ploder","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2124","DOI":"10.1016\/j.ophtha.2014.06.006","article-title":"Personalized diagnosis and management of congenital cataract by next-generation sequencing","volume":"121","author":"Gillespie","year":"2014","journal-title":"Ophthalmology"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Harding, P., and Moosajee, M. (2019). The Molecular Basis of Human Anophthalmia and Microphthalmia. J. Dev. Biol., 7.","DOI":"10.3390\/jdb7030016"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1055\/s-0036-1592350","article-title":"Genetic Advances in Microphthalmia","volume":"5","author":"Plaisancie","year":"2016","journal-title":"J. Pediatr. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.ejmg.2014.05.002","article-title":"The genetic architecture of microphthalmia, anophthalmia and coloboma","volume":"57","author":"Williamson","year":"2014","journal-title":"Eur. J. Med. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1038\/ejhg.2011.233","article-title":"Genomic imbalances detected by array-CGH in patients with syndromal ocular developmental anomalies","volume":"20","author":"Delahaye","year":"2012","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1097\/GIM.0b013e318204cfd2","article-title":"Array comparative genomic hybridization analysis in patients with anophthalmia, microphthalmia, and coloboma","volume":"13","author":"Raca","year":"2011","journal-title":"Genet. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2706","DOI":"10.1002\/ajmg.a.33098","article-title":"Novel SOX2 mutations and genotype-phenotype correlation in anophthalmia and microphthalmia","volume":"149A","author":"Schneider","year":"2009","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Plaisanci\u00e9, J., Ceroni, F., Holt, R., Zazo Seco, C., Calvas, P., Chassaing, N., and Ragge, N.K. (2019). Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia\/microphthalmia. Hum. Genet., 1\u201332.","DOI":"10.1007\/s00439-019-01977-y"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1002\/(SICI)1096-8628(19980217)75:5<497::AID-AJMG8>3.0.CO;2-K","article-title":"Congenital eye malformations: Clinical-epidemiological analysis of 1,124,654 consecutive births in Spain","volume":"75","author":"Bermejo","year":"1998","journal-title":"Am. J. Med. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1097\/01.ede.0000158817.43037.ab","article-title":"Eye anomalies: Seasonal variation and maternal viral infections","volume":"16","author":"Busby","year":"2005","journal-title":"Epidemiology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/0039-6257(91)90107-Q","article-title":"Ocular teratology","volume":"35","author":"Miller","year":"1991","journal-title":"Surv. Ophthalmol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/mgg3.2","article-title":"Clinical and mutation analysis of 51 probands with anophthalmia and\/or severe microphthalmia from a single center","volume":"1","author":"Williamson","year":"2013","journal-title":"Mol. Genet. Genomic Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1111\/cge.12275","article-title":"Molecular findings and clinical data in a cohort of 150 patients with anophthalmia\/microphthalmia","volume":"86","author":"Chassaing","year":"2014","journal-title":"Clin. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Jackson, D., Malka, S., Harding, P., Palma, J., Dunbar, H., and Moosajee, M. (2020). Molecular diagnostic challenges for non-retinal developmental eye disorders in the United Kingdom. Am. J. Med. Genet. Part C Semin. Med. Genet., 1\u201312.","DOI":"10.1002\/ajmg.c.31837"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"16017","DOI":"10.1074\/jbc.M709934200","article-title":"Identification and functional analysis of phosphorylated tyrosine residues within EphA2 receptor tyrosine kinase","volume":"283","author":"Fang","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1111\/cge.12543","article-title":"Exome Sequencing in 32 Patients with Anophthalmia\/ Microphthalmia and Developmental Eye Defects","volume":"88","author":"Slavotinek","year":"2015","journal-title":"Clin. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1002\/ajmg.a.40352","article-title":"Epidemiology of anophthalmia and microphthalmia: Prevalence and patterns in Texas, 1999\u20132009","volume":"176","author":"Chambers","year":"2018","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1007\/s10384-012-0126-7","article-title":"Survey of microphthalmia in Japan","volume":"56","author":"Nishina","year":"2012","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Haug, P., Koller, S., Maggi, J., Lang, E., Feil, S., Wlodarczyk, A., B\u00e4hr, L., Steindl, K., Rohrbach, M., and Gerth-Kahlert, C. (2021). Whole Exome Sequencing in Coloboma\/Microphthalmia: Identification of Novel and Recurrent Variants in Seven Genes. Genes, 12.","DOI":"10.3390\/genes12010065"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1093\/hmg\/ddl120","article-title":"Nance-Horan syndrome protein, NHS, associates with epithelial cell junctions","volume":"15","author":"Sharma","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1242\/dev.129.1.167","article-title":"Disruption of Gja8 (\u03b18 connexin) in mice leads to microphthalmia associated with retardation of lens growth and lens fiber maturation","volume":"129","author":"Rong","year":"2002","journal-title":"Development"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2033","DOI":"10.1242\/dev.02361","article-title":"Diverse gap junctions modulate distinct mechanisms for fiber cell formation during lens development and cataractogenesis","volume":"133","author":"Xia","year":"2006","journal-title":"Development"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4237","DOI":"10.1242\/dev.100727","article-title":"EphA2 and Src regulate equatorial cell morphogenesis during lens development","volume":"140","author":"Cheng","year":"2013","journal-title":"Development"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"7245","DOI":"10.1073\/pnas.1917922117","article-title":"Rbm24 controls poly(A) tail length and translation efficiency of crystallin mRNAs in the lens via cytoplasmic polyadenylation","volume":"117","author":"Shao","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Zhang, J., Cui, W.-W., Du, C., Huang, Y., Pi, X., Guo, W., Wang, J., Huang, W., Chen, D., and Li, J. (2020). Knockout of DNase1l1l abrogates lens denucleation process and causes cataract in zebrafish. Biochim. Biophys. Acta Mol. Basis Dis., 1866.","DOI":"10.1016\/j.bbadis.2020.165724"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1016\/j.ophtha.2018.12.050","article-title":"The Oculome Panel Test: Next-Generation Sequencing to Diagnose a Diverse Range of Genetic Developmental Eye Disorders","volume":"126","author":"Patel","year":"2019","journal-title":"Ophthalmology"},{"key":"ref_53","unstructured":"Westerfield, M. (2000). The Zebrafish Book: A Guide for the Laboratory Use of Zebrafish (Danio Rerio), Institute of Neuroscience. University of Oregon."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/aja.1002030302","article-title":"Stages of embryonic development of the zebrafish","volume":"203","author":"Kimmel","year":"1995","journal-title":"Dev. Dyn."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"5292","DOI":"10.1038\/onc.2012.571","article-title":"Involvement of EphA2-mediated tyrosine phosphorylation of Shp2 in Shp2-regulated activation of extracellular signal-regulated kinase","volume":"32","author":"Miura","year":"2013","journal-title":"Oncogene"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/2190\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:26:43Z","timestamp":1760160403000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/2190"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,22]]},"references-count":55,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["ijms22042190"],"URL":"https:\/\/doi.org\/10.3390\/ijms22042190","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,22]]}}}