{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:21:16Z","timestamp":1790187676558,"version":"4.1.0"},"reference-count":56,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2020,8,27]],"date-time":"2020-08-27T00:00:00Z","timestamp":1598486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Congenital adrenal hyperplasia (CAH) consists of several autosomal recessive disorders that inhibit steroid biosynthesis. We describe a case report diagnosed with adrenal insufficiency due to low adrenal steroids and adrenocorticotropic hormone excess due to lack of cortisol negative feedback signaling to the pituary gland. Genetic work up revealed two missense variants, p.Thr204Arg and p.Leu260Arg in the STAR gene, inherited by both parents (non-consanguineous). The StAR protein supports CYP11A1 enzyme to cleave the side chain of cholesterol and synthesize pregnenolone which is metabolized to all steroid hormones. We used bioinformatics to predict the impact of the variants on StAR activity and then we performed functional tests to characterize the two novel variants. In a cell system we tested the ability of variants to support cholesterol conversion to pregnenolone and measured their mRNA and protein expression. For both variants, we observed loss of StAR function, reduced protein expression and categorized them as pathogenic variants according to guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. These results fit the phenotype of the girl during diagnosis. This study characterizes two novel variants and expands the list of missense variants that cause CAH.<\/jats:p>","DOI":"10.3390\/ijms21176185","type":"journal-article","created":{"date-parts":[[2020,8,27]],"date-time":"2020-08-27T08:05:18Z","timestamp":1598515518000},"page":"6185","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Characterization of Two Novel Variants of the Steroidogenic Acute Regulatory Protein Identified in a Girl with Classic Lipoid Congenital Adrenal Hyperplasia"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3078-2176","authenticated-orcid":false,"given":"Efstathios","family":"Katharopoulos","sequence":"first","affiliation":[{"name":"Department of Paediatrics, Division of Endocrinology, Diabetology &amp; Metabolism, Bern University Hospital, 3010 Bern, Switzerland"},{"name":"Department of Biomedical Research, Bern University Hospital and University of Bern, 3010 Bern, Switzerland"},{"name":"Graduate School Bern, University of Bern, 3012 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natascia","family":"Di Iorgi","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Istituto Giannina Gaslini, University of Genoa, 16147 Genoa, Italy"},{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2695-3531","authenticated-orcid":false,"given":"Paula","family":"Fernandez-Alvarez","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Genetics and Rare Disease Unit, University Hospital Vall d\u2019Hebron, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8331-5902","authenticated-orcid":false,"given":"Amit V.","family":"Pandey","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Division of Endocrinology, Diabetology &amp; Metabolism, Bern University Hospital, 3010 Bern, Switzerland"},{"name":"Department of Biomedical Research, Bern University Hospital and University of Bern, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Groessl","sequence":"additional","affiliation":[{"name":"Department of Biomedical Research, Bern University Hospital and University of Bern, 3010 Bern, Switzerland"},{"name":"Department of Nephrology and Hypertension, Bern University Hospital, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shraddha","family":"Dubey","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Division of Endocrinology, Diabetology &amp; Metabolism, Bern University Hospital, 3010 Bern, Switzerland"},{"name":"Department of Biomedical Research, Bern University Hospital and University of Bern, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N\u00faria","family":"Camats","sequence":"additional","affiliation":[{"name":"Growth and Development Research Unit, Vall d\u2019Hebron Research Institute (VHIR), Centre of Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia","family":"Napoli","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Istituto Giannina Gaslini, University of Genoa, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppa","family":"Patti","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Istituto Giannina Gaslini, University of Genoa, 16147 Genoa, Italy"},{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilea","family":"Lezzi","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Istituto Giannina Gaslini, University of Genoa, 16147 Genoa, Italy"},{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7183-5238","authenticated-orcid":false,"given":"Mohamad","family":"Maghnie","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Istituto Giannina Gaslini, University of Genoa, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christa E.","family":"Fl\u00fcck","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Division of Endocrinology, Diabetology &amp; 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J. Endocrinol."},{"key":"ref_3","first-page":"397","article-title":"The syndrome of male pseudohermaphrodism in congenital adrenocortical hyperplasia without overproduction of androgens (adrenal male pseudohermaphrodism)","volume":"10","author":"Prader","year":"1955","journal-title":"Helv. Paediatr. Acta"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1126\/science.7892608","article-title":"Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis","volume":"267","author":"Lin","year":"1995","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1677\/jme.0.0190227","article-title":"Congenital lipoid adrenal hyperplasia: The human gene knockout for the steroidogenic acute regulatory protein","volume":"19","author":"Miller","year":"1997","journal-title":"J. Mol. Endocrinol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"47123","DOI":"10.1074\/jbc.M206965200","article-title":"Transfer of cholesterol between phospholipid vesicles mediated by the steroidogenic acute regulatory protein (StAR)","volume":"277","author":"Tuckey","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1210\/me.2012-1159","article-title":"Identification of a Dynamic Mitochondrial Protein Complex Driving Cholesterol Import, Trafficking, and Metabolism to Steroid Hormones","volume":"26","author":"Rone","year":"2012","journal-title":"Mol. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.jsbmb.2016.03.009","article-title":"Disorders in the initial steps of steroid hormone synthesis","volume":"165","author":"Miller","year":"2017","journal-title":"J. Steroid Biol. Mol. Endocrinol."},{"key":"ref_9","first-page":"1","article-title":"Mechanistic sequence of mitochondrial cholesterol transport by star proteins","volume":"2","author":"Bose","year":"2011","journal-title":"J. Proteins Proteom."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"22183","DOI":"10.1074\/jbc.R300003200","article-title":"StAR-related lipid transfer (START) proteins: Mediators of intracellular lipid metabolism","volume":"278","author":"Soccio","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4778","DOI":"10.1073\/pnas.92.11.4778","article-title":"Human steroidogenic acute regulatory protein: Functional activity in COS-1 cells, tissue-specific expression, and mapping of the structural gene to 8p11.2 and a pseudogene to chromosome 13","volume":"92","author":"Sugawara","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4261","DOI":"10.1074\/jbc.M006279200","article-title":"The steroidogenic acute regulatory protein homolog MLN64, a late endosomal cholesterol-binding protein","volume":"276","author":"Alpy","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"11722","DOI":"10.1021\/bi000911l","article-title":"N-218 MLN64, a protein with StAR-like steroidogenic activity, is folded and cleaved similarly to StAR","volume":"39","author":"Bose","year":"2000","journal-title":"Biochemistry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8462","DOI":"10.1073\/pnas.94.16.8462","article-title":"MLN64 contains a domain with homology to the steroidogenic acute regulatory protein (StAR) that stimulates steroidogenesis","volume":"94","author":"Watari","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.1194\/jlr.E008854","article-title":"STARTing to understand MLN64 function in cholesterol transport","volume":"51","author":"Rigotti","year":"2010","journal-title":"J. Lipid Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1056\/NEJM199612193352503","article-title":"The pathophysiology and genetics of congenital lipoid adrenal hyperplasia","volume":"335","author":"Bose","year":"1996","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1136\/adc.30.154.538","article-title":"A form of lipoidosis of the adrenal cortex in an infant","volume":"30","author":"Sandison","year":"1955","journal-title":"Arch. Dis. Child."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4781","DOI":"10.1210\/jc.2006-1565","article-title":"Nonclassic congenital lipoid adrenal hyperplasia: A new disorder of the steroidogenic acute regulatory protein with very late presentation and normal male genitalia","volume":"91","author":"Baker","year":"2006","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3865","DOI":"10.1210\/jc.2009-0467","article-title":"Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency","volume":"94","author":"Metherell","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1111\/j.1365-2265.1985.tb01107.x","article-title":"Congenital adrenal hyperplasia due to deficient cholesterol side-chain cleavage activity (20, 22-desmolase) in a patient treated for 18 years","volume":"23","author":"Hauffa","year":"1985","journal-title":"Clin. Endocrinol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Simoni, M., and Huhtaniemi, I.T. (2017). Testicular steroidogenesis. Endocrinology of the Testis and Male Reproduction, Springer International Publishing.","DOI":"10.1007\/978-3-319-44441-3"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"527","DOI":"10.3389\/fnins.2016.00527","article-title":"Thirty-Eight-Year Follow-Up of Two Sibling Lipoid Congenital Adrenal Hyperplasia Patients Due to Homozygous Steroidogenic Acute Regulatory (STARD1) Protein Mutation. Molecular Structure and Modeling of the STARD1 L275P Mutation","volume":"10","author":"Khoury","year":"2016","journal-title":"Front. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1194\/jlr.R016675","article-title":"Early steps in steroidogenesis: Intracellular cholesterol trafficking","volume":"52","author":"Miller","year":"2011","journal-title":"J. Lipid Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.coemr.2019.08.005","article-title":"Update on genetics of primary adrenal insufficiency","volume":"8","year":"2019","journal-title":"Curr. Opin. Endocr. Metab. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5304","DOI":"10.1210\/jc.2005-0874","article-title":"A novel mutation L260P of the steroidogenic acute regulatory protein gene in three unrelated patients of Swiss ancestry with congenital lipoid adrenal hyperplasia","volume":"90","author":"Fluck","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1093\/hmg\/6.4.571","article-title":"Analysis of the steroidogenic acute regulatory protein (StAR) gene in Japanese patients with congenital lipoid adrenal hyperplasia","volume":"6","author":"Nakae","year":"1997","journal-title":"Hum. Mol. Genet."},{"key":"ref_28","first-page":"150119","article-title":"Lipoid congenital adrenal hyperplasia due to STAR mutations in a Caucasian patient","volume":"2016","author":"Kaur","year":"2016","journal-title":"Endocrinol. Diabetes Metab. Case Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.yjmcc.2013.11.006","article-title":"Proteasomal and lysosomal protein degradation and heart disease","volume":"71","author":"Wang","year":"2014","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Fluck, C.E., Pandey, A.V., Dick, B., Camats, N., Fernandez-Cancio, M., Clemente, M., Gussinye, M., Carrascosa, A., Mullis, P.E., and Audi, L. (2011). Characterization of novel StAR (steroidogenic acute regulatory protein) mutations causing non-classic lipoid adrenal hyperplasia. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0020178"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1507\/endocrj.47.629","article-title":"Genetic and endocrinological evaluations of three 46,XX patients with congenital lipoid adrenal hyperplasia previously reported as having presented spontaneous puberty","volume":"47","author":"Tanae","year":"2000","journal-title":"Endocr. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"934.e915","DOI":"10.1016\/j.fertnstert.2008.07.1770","article-title":"Conception and pregnancy outcome in a patient with 11-bp deletion of the steroidogenic acute regulatory protein gene","volume":"91","author":"Sertedaki","year":"2009","journal-title":"Fertil. Steril."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"723","DOI":"10.3389\/fendo.2019.00723","article-title":"Assisted Reproduction in Congenital Adrenal Hyperplasia","volume":"10","author":"Chatziaggelou","year":"2019","journal-title":"Front. Endocriol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1210\/jc.2015-3201","article-title":"Successful Live Birth in a Woman With 17alpha-Hydroxylase Deficiency Through IVF Frozen-Thawed Embryo Transfer","volume":"101","author":"Bianchi","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"158609","DOI":"10.1016\/j.bbalip.2020.158609","article-title":"Stable reduction of STARD4 alters cholesterol regulation and lipid homeostasis","volume":"1865","author":"Iaea","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1194\/jlr.M091967","article-title":"StarD5: An ER stress protein regulates plasma membrane and intracellular cholesterol homeostasis","volume":"60","author":"Malacrida","year":"2019","journal-title":"J. Lipid Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6943","DOI":"10.1073\/pnas.052143799","article-title":"The cholesterol-regulated StarD4 gene encodes a StAR-related lipid transfer protein with two closely related homologues, StarD5 and StarD6","volume":"99","author":"Soccio","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1097\/MPG.0b013e3181da213e","article-title":"Neonatal anthropometric charts: The Italian neonatal study compared with other European studies","volume":"51","author":"Bertino","year":"2010","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1136\/adc.51.3.170","article-title":"Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty","volume":"51","author":"Tanner","year":"1976","journal-title":"Arch. Dis. Child."},{"key":"ref_40","unstructured":"WHO Multicentre Growth Reference Study Group (2006). WHO Child Growth Standards: Length\/Height-for-Age, Weight-for-Age, Weight-for-Length, Weight-for-Height and Body Mass Index-for-Age: Methods and Development, World Health Organization."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Thorsell, A.G., Lee, W.H., Persson, C., Siponen, M.I., Nilsson, M., Busam, R.D., Kotenyova, T., Sch\u00fcler, H., and Lehti\u00f6, L. (2011). Comparative structural analysis of lipid binding START domains. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0019521"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1002\/prot.20251","article-title":"Making optimal use of empirical energy functions: Force-field parameterization in crystal space","volume":"57","author":"Krieger","year":"2004","journal-title":"Proteins"},{"key":"ref_44","unstructured":"(2020, July 24). The PyMOL Molecular Graphics System, Version 1.2r3pre. Schr\u00f6dinger, LLC. Available online: www.pymol.org."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_46","unstructured":"Case, D.A., Belfon, K., Ben-Shalom, I.Y., Brozell, S.R., Cerutti, D.S., Cheatham, T.E., Cruzeiro, V.W.D., Darden, T.A., Duke, R.E., and Giambasu, G. (2020). Amber20, University of California."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0065-3233(03)66002-X","article-title":"Force fields for protein simulations","volume":"66","author":"Ponder","year":"2003","journal-title":"Adv. Protein Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"W229","DOI":"10.1093\/nar\/gkx439","article-title":"SDM: A server for predicting effects of mutations on protein stability","volume":"45","author":"Pandurangan","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1002\/humu.22965","article-title":"UMD-Predictor: A High-Throughput Sequencing Compliant System for Pathogenicity Prediction of any Human cDNA Substitution","volume":"37","author":"Salgado","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"W452","DOI":"10.1093\/nar\/gks539","article-title":"SIFT web server: Predicting effects of amino acid substitutions on proteins","volume":"40","author":"Sim","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1093\/bioinformatics\/btv195","article-title":"Provean web server: A tool to predict the functional effect of amino acid substitutions and indels","volume":"31","author":"Choi","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: Mutation prediction for the deep-sequencing age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat. Methods"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e118","DOI":"10.1093\/nar\/gkr407","article-title":"Predicting the functional impact of protein mutations: Application to cancer genomics","volume":"39","author":"Reva","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1089\/dna.1993.12.371","article-title":"Construction and function of fusion enzymes of the human cytochrome P450scc system","volume":"12","author":"Harikrishna","year":"1993","journal-title":"DNA Cell Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/17\/6185\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:07:27Z","timestamp":1760177247000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/17\/6185"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,27]]},"references-count":56,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["ijms21176185"],"URL":"https:\/\/doi.org\/10.3390\/ijms21176185","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,27]]}}}