{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T16:56:54Z","timestamp":1762102614012,"version":"build-2065373602"},"reference-count":54,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T00:00:00Z","timestamp":1613692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007052","name":"Universit\u00e0 degli Studi di Verona","doi-asserted-by":"publisher","award":["JPVR184ZZ5"],"award-info":[{"award-number":["JPVR184ZZ5"]}],"id":[{"id":"10.13039\/501100007052","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We present a long-term follow-up in autosomal dominant gyrate atrophy-like choroidal dystrophy (adGALCD) and propose a possible genotype\/phenotype correlation. Ophthalmic examination of six patients from two families revealed confluent areas of choroidal atrophy resembling gyrate atrophy, starting in the second decade of life. Progression continued centrally, reaching the fovea at about 60 years of age. Subretinal deposits, retinal pigmentation or choroidal neovascularization as seen in late-onset retinal degeneration (LORD) were not observed. Whole genome sequencing revealed a novel missense variant in the C1QTNF5 gene (p.(Q180E)) which was found in heterozygous state in all affected subjects. Haplotype analysis showed that this variant found in both families is identical by descent. Three-dimensional modeling of the possible supramolecular assemblies of C1QTNF5 revealed that the p.(Q180E) variant led to the destabilization of protein tertiary and quaternary structures, affecting both the stability of the single protomer and the entire globular head, thus exerting detrimental effects on the formation of C1QTNF5 trimeric globular domains and their interaction. In conclusion, we propose that the p.(Q180E) variant causes a specific phenotype, adGALCD, that differs in multiple clinical aspects from LORD. Disruption of optimal cell-adhesion mechanisms is expected when analyzing the effects of the point mutation at the protein level.<\/jats:p>","DOI":"10.3390\/ijms22042089","type":"journal-article","created":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T20:54:08Z","timestamp":1613768048000},"page":"2089","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Autosomal Dominant Gyrate Atrophy-Like Choroidal Dystrophy Revisited: 45 Years Follow-Up and Association with a Novel C1QTNF5 Missense Variant"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5221-4631","authenticated-orcid":false,"given":"Ulrich","family":"Kellner","sequence":"first","affiliation":[{"name":"Zentrum f\u00fcr Seltene Netzhauterkrankungen, AugenZentrum Siegburg, MVZ Augen\u00e4rztliches Diagnostik- und Therapiecentrum Siegburg GmbH, Europaplatz 3, 53721 Siegburg, Germany"},{"name":"RetinaScience, Postfach 301212, 53192 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"Weisschuh","sequence":"additional","affiliation":[{"name":"Center for Ophthalmology, Institute for Ophthalmic Research, University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silke","family":"Weinitz","sequence":"additional","affiliation":[{"name":"Zentrum f\u00fcr Seltene Netzhauterkrankungen, AugenZentrum Siegburg, MVZ Augen\u00e4rztliches Diagnostik- und Therapiecentrum Siegburg GmbH, Europaplatz 3, 53721 Siegburg, Germany"},{"name":"RetinaScience, Postfach 301212, 53192 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ghazaleh","family":"Farmand","sequence":"additional","affiliation":[{"name":"Zentrum f\u00fcr Seltene Netzhauterkrankungen, AugenZentrum Siegburg, MVZ Augen\u00e4rztliches Diagnostik- und Therapiecentrum Siegburg GmbH, Europaplatz 3, 53721 Siegburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6092-2398","authenticated-orcid":false,"given":"Sebastian","family":"Deutsch","sequence":"additional","affiliation":[{"name":"Zentrum f\u00fcr Seltene Netzhauterkrankungen, AugenZentrum Siegburg, MVZ Augen\u00e4rztliches Diagnostik- und Therapiecentrum Siegburg GmbH, Europaplatz 3, 53721 Siegburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Friederike","family":"Kort\u00fcm","sequence":"additional","affiliation":[{"name":"Center for Ophthalmology, University Eye Hospital, University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pascale","family":"Mazzola","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin","family":"Sch\u00e4ferhoff","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7821-3717","authenticated-orcid":false,"given":"Valerio","family":"Marino","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, 37134 Verona, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3724-3044","authenticated-orcid":false,"given":"Daniele","family":"Dell\u2019Orco","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, 37134 Verona, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"140555","DOI":"10.1016\/j.bbapap.2020.140555","article-title":"Deficit of human ornithine aminotransferase in gyrate atrophy: Molecular, cellular, and clinical aspects","volume":"1869","author":"Montioli","year":"2021","journal-title":"Biochim. Biophys. Acta BBA Proteins Proteom."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1136\/bjophthalmol-2020-316028","article-title":"Long-term natural history of visual acuity in eyes with choroideremia: A systematic review and meta-analysis of data from 1004 individual eyes","volume":"105","author":"Shen","year":"2021","journal-title":"Br. J. Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1038\/ejhg.2011.86","article-title":"A dominant mutation in RPE65 identified by whole-exome sequencing causes retinitis pigmentosa with choroidal involvement","volume":"19","author":"Bowne","year":"2011","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1007\/s10633-019-09705-7","article-title":"Late-onset night blindness with peripheral flecks accompanied by progressive trickle-like macular degeneration","volume":"139","author":"Tsunoda","year":"2019","journal-title":"Doc. Ophthalmol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1097\/00006982-198500510-00007","article-title":"Differential diagnosis of diffuse choroidal atrophies","volume":"5","author":"Hayasaka","year":"1985","journal-title":"Retina"},{"key":"ref_6","unstructured":"Marchesani, O., and Sautter, H. (1957). Atlas des Augenhintergrundes, Urban & Schwarzenberg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1097\/00006982-199717050-00008","article-title":"Gyrate atrophy-like phenotype with normal plasma ornithine","volume":"17","author":"Kellner","year":"1997","journal-title":"Retina"},{"key":"ref_8","first-page":"1772","article-title":"Sub-retinal pigment epithelial deposits in a dominant late-onset retinal degeneration","volume":"37","author":"Kuntz","year":"1996","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/BF02143075","article-title":"Extensive subretinal pigment epithelial deposit in two brothers suffering from dominant retinitis pigmentosa","volume":"224","author":"Duvall","year":"1986","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/S0161-6420(94)31358-3","article-title":"Pathology of hereditary retinal degeneration associated with hypobetalipoproteinemia","volume":"101","author":"Brosnahan","year":"1994","journal-title":"Ophthalmology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2657","DOI":"10.1093\/hmg\/ddg289","article-title":"Mutation in a short-chain collagen gene, CTRP5, results in extracellular deposit formation in late-onset retinal degeneration: A genetic model for age-related macular degeneration","volume":"12","author":"Hayward","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"12147","DOI":"10.1038\/s41598-017-11898-3","article-title":"Novel pathogenic mutations in C1QTNF5 support a dominant negative disease mechanism in late-onset retinal degeneration","volume":"7","author":"Stanton","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1080\/13816810.2018.1546406","article-title":"Whole genome sequencing reveals novel mutations causing autosomal dominant inherited macular degeneration","volume":"39","author":"Borooah","year":"2018","journal-title":"Ophthalmic Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1042\/BJ20081240","article-title":"Molecular, biochemical and functional characterizations of C1q\/TNF family members: Adipose-tissue-selective expression patterns, regulation by PPAR-\u03b3 agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions","volume":"416","author":"Wong","year":"2008","journal-title":"Biochem. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5505","DOI":"10.1167\/iovs.06-0312","article-title":"CTRP5 is a membrane-associated and secretory protein in the rpe and ciliary body and the S163R mutation of CTRP5 impairs its secretion","volume":"47","author":"Mandal","year":"2006","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.jsb.2012.07.011","article-title":"Crystal structure of the globular domain of C1QTNF5: Implications for late-onset retinal macular degeneration","volume":"180","author":"Tu","year":"2012","journal-title":"J. Struct. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1093\/hmg\/ddl091","article-title":"Disease mechanisms in late-onset retinal macular degeneration associated with mutation in C1QTNF5","volume":"15","author":"Shu","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.jsb.2014.02.001","article-title":"The macular degeneration-linked C1QTNF5 (S163) mutation causes higher-order structural rearrangements","volume":"186","author":"Tu","year":"2014","journal-title":"J. Struct. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/S0960-9822(98)70133-2","article-title":"The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor","volume":"8","author":"Shapiro","year":"1998","journal-title":"Curr. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1529\/biophysj.104.049189","article-title":"Electrostatic contributions to the kinetics and thermodynamics of protein assembly","volume":"88","author":"Xue","year":"2005","journal-title":"Biophys. J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2256","DOI":"10.1016\/S0161-6420(00)00419-X","article-title":"Dominant late-onset retinal degeneration with regional variation of sub-retinal pigment epithelium deposits, retinal function, and photoreceptor degeneration","volume":"107","author":"Milam","year":"2000","journal-title":"Ophthalmology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1136\/bjo.2008.150151","article-title":"Late-onset retinal macular degeneration: Clinical insights into an inherited retinal degeneration","volume":"85","author":"Borooah","year":"2009","journal-title":"Postgrad. Med. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1097\/IAE.0b013e318240a574","article-title":"The characterization of retinal phenotype in a family with c1qtnf5-related late-onset retinal degeneration","volume":"32","author":"Vincent","year":"2012","journal-title":"Retina"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1038\/s41433-019-0348-8","article-title":"Multimodal imaging of late-onset retinal degeneration complicated by bilateral choroidal neovascularization","volume":"33","author":"Mandal","year":"2019","journal-title":"Eye"},{"key":"ref_25","unstructured":"Papastavrou, V.T., O\u2019Brien, J.M., Regan, A.J., Aftab, A.M., and Browning, A.C. (2020). The progression of macular structural and func-tional changes in late-onset retinal degeneration. Retin. Cases Brief. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Borooah, S., Papastavrou, V.T., Browning, A.C., Lando, L., Moghimi, S., Lin, T., Dans, K., Motevasseli, T., Cameron, J.R., and Freeman, W.R. (2020). Characterizing the natural history of foveal-sparing atrophic late-onset retinal degeneration. Retina.","DOI":"10.1097\/IAE.0000000000003017"},{"key":"ref_27","first-page":"284","article-title":"Late-onset retinal macular degeneration: Clinical insights into an inherited retinal degeneration","volume":"93","author":"Borooah","year":"2009","journal-title":"Br. J. Ophthalmol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3363","DOI":"10.1167\/iovs.05-0159","article-title":"Late-onset macular degeneration and long anterior lens zonules result from ACTRP5gene mutation","volume":"46","author":"Ayyagari","year":"2005","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1167\/tvst.9.6.26","article-title":"Quantifying the separation between the retinal pigment epithelium and bruch\u2019s membrane using optical coherence tomography in patients with inherited macular degeneration","volume":"9","author":"Khan","year":"2020","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.oret.2018.11.010","article-title":"Choroidal neovascularization in late-onset retinal macular degeneration","volume":"3","author":"Ramtohul","year":"2019","journal-title":"Ophthalmol. Retin."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.1097\/IAE.0000000000001113","article-title":"Longitudinal structural changes in late-onset retinal degeneration","volume":"36","author":"Cukras","year":"2016","journal-title":"Retina"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e191","DOI":"10.1111\/aos.12010","article-title":"Phenotypic findings inC1QTNF5retinopathy (late-onset retinal degeneration)","volume":"91","author":"Soumplis","year":"2013","journal-title":"Acta Ophthalmol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.jcjo.2014.12.001","article-title":"Improvement of retinal function in L-ORD after prolonged dark adaptation","volume":"50","author":"Papastavrou","year":"2015","journal-title":"Can. J. Ophthalmol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e67","DOI":"10.1016\/j.jfo.2014.05.023","article-title":"Traitement d\u2019une membrane n\u00e9ovasculaire choro\u00efdienne chez un patient pr\u00e9sentant une dystrophie r\u00e9tinienne autosomique dominante rare par aflibercept: \u00c0 propos d\u2019un cas","volume":"38","author":"Troumani","year":"2015","journal-title":"J. Fran\u00e7ais d\u2019Ophtalmol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1038\/eye.2010.71","article-title":"Treatment of a choroidal neovascular membrane in a patient with late-onset retinal degeneration (L-ORD) with intravitreal Ranibizumab","volume":"24","author":"Aye","year":"2010","journal-title":"Eye"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1001\/jamaophthalmol.2014.2059","article-title":"Late-onset retinal degeneration caused byC1QTNF5mutation","volume":"132","author":"Jacobson","year":"2014","journal-title":"JAMA Ophthalmol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Almoguera, B., Li, J., Garcia-Sandoval, B., Guo, Y., Tian, L., Liu, X., Guan, L., Zhang, J., Keating, B., and Xu, X. (2015). Application of whole exome sequencing in six families with an initial diagnosis of autosomal dominant retinitis pigmentosa: Lessons learned. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0133624"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1001\/archopht.118.1.85","article-title":"Autosomal dominant hemorrhagic macular dystrophy not associated with the TIMP3 gene","volume":"118","author":"Ayyagari","year":"2000","journal-title":"Arch. Ophthalmol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1016\/j.ajo.2005.06.023","article-title":"Long anterior lens zonules in late-onset retinal degeneration (L-ORD)","volume":"140","author":"Subrayan","year":"2005","journal-title":"Am. J. Ophthalmol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1097\/IJG.0b013e31815c3b04","article-title":"Possible association between long anterior lens zonules and plateau iris configuration","volume":"17","author":"Roberts","year":"2008","journal-title":"J. Glaucoma"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.jcrs.2017.05.041","article-title":"Cataract surgery in patients with late-onset retinal degeneration","volume":"43","author":"Papastavrou","year":"2017","journal-title":"J. Cataract. Refract. Surg."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5514","DOI":"10.1167\/iovs.06-0449","article-title":"Spatial and temporal expression of MFRP and its interaction with CTRP5","volume":"47","author":"Mandal","year":"2006","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e13011","DOI":"10.1111\/acel.13011","article-title":"Late-onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1","volume":"18","author":"Chekuri","year":"2019","journal-title":"Aging Cell"},{"key":"ref_44","first-page":"61","article-title":"Co-expression of wild-type and mutant S163R C1QTNF5 in retinal pigment epithelium","volume":"1074","author":"Dinculescu","year":"2018","journal-title":"Results Probl. Cell Differ."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6971","DOI":"10.1167\/iovs.15-17166","article-title":"Pathological effects of mutant C1QTNF5 (S163R) expression in murine retinal pigment epithelium","volume":"56","author":"Dinculescu","year":"2015","journal-title":"Investig. Opthalmol.Vis. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"92","DOI":"10.3389\/fncel.2020.00092","article-title":"Photoreceptor disc enclosure occurs in the absence of normal peripherin-2\/RDS oligomerization","volume":"14","author":"Lewis","year":"2020","journal-title":"Front. Cell. Neurosci."},{"key":"ref_47","first-page":"2438","article-title":"Hetero-oligomeric interactions of an ELOVL4 mutant protein: Implications in the molecular mechanism of Stargardt-3 macular dystrophy","volume":"16","author":"Okuda","year":"2010","journal-title":"Mol. Vis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1001\/jamaophthalmol.2020.4206","article-title":"Clinical phenotype and course of pde6a-associated retinitis pigmentosa disease, characterized in preparation for a gene supplementation trial","volume":"138","author":"Kuehlewein","year":"2020","journal-title":"JAMA Ophthalmol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"201","DOI":"10.3109\/13816810.2015.1033556","article-title":"Fundus autofluorescence and SD-oct document rapid progression in autosomal dominant vitreoretinochoroidopathy (ADVIRC) Associated with a C.256G> A mutation in BEST1","volume":"37","author":"Kellner","year":"2016","journal-title":"Ophthalmic Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10633-011-9296-8","article-title":"ISCEV standard for clinical multifocal electroretinography (mfERG) (2011 edition)","volume":"124","author":"Hood","year":"2011","journal-title":"Doc. Ophthalmol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10633-014-9473-7","article-title":"ISCEV Standard for full-field clinical electroretinography (2015 update)","volume":"130","author":"McCulloch","year":"2015","journal-title":"Doc. Ophthalmol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12881-020-01166-z","article-title":"First submicroscopic inversion of the OPA1 gene identified in dominant optic atrophy\u2013a case report","volume":"21","author":"Weisschuh","year":"2020","journal-title":"BMC Med. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1002\/humu.23311","article-title":"CNGB3 mutation spectrum including copy number variations in 552 achromatopsia patients","volume":"38","author":"Mayer","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1002\/prot.25594","article-title":"AggScore: Prediction of aggregation-prone regions in proteins based on the distribution of surface patches","volume":"86","author":"Sankar","year":"2018","journal-title":"Proteins Struct. Funct. Bioinform."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/2089\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:26:33Z","timestamp":1760160393000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/2089"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,19]]},"references-count":54,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["ijms22042089"],"URL":"https:\/\/doi.org\/10.3390\/ijms22042089","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2021,2,19]]}}}