{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T04:32:25Z","timestamp":1793421145432,"version":"4.5.0"},"reference-count":39,"publisher":"Zoological Society of Japan","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Zoological Science"],"published-print":{"date-parts":[[2024,4,8]]},"abstract":"<jats:p>cytochrome P-450, 21-hydroxylase (cyp21a2), encodes an enzyme required for cortisol biosynthesis, and its mutations are the major genetic cause of congenital adrenal hyperplasia (CAH) in humans. Here, we have generated a null allele for the medaka cyp21a2 with a nine base-pair insertion which led to a truncated protein. We have observed a delay in hatching and a low survival rate in homozygous mutants. The interrenal gland (adrenal counterpart in teleosts) exhibits hyperplasia and the number of pomca-expressing cells in the pituitary increases in the homozygous mutant. A mass spectrometry-based analysis of whole larvae confirmed a lack of cortisol biosynthesis, while its corresponding precursors were significantly increased, indicating a systemic glucocorticoid deficiency in our mutant model. Furthermore, these phenotypes at the larval stage are rescued by cortisol. In addition, females showed complete sterility with accumulated follicles in the ovary while male homozygous mutants were fully fertile in the adult mutants. These results demonstrate that the mutant medaka recapitulates several aspects of cyp21a2-deficiency observed in humans, making it a valuable model for studying steroidogenesis in CAH.<\/jats:p>","DOI":"10.2108\/zs230107","type":"journal-article","created":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T05:00:55Z","timestamp":1712120455000},"page":"263-274","source":"Crossref","is-referenced-by-count":1,"title":["Genetic Disruption of cyp21a2 Leads to Systemic Glucocorticoid Deficiency and Tissues Hyperplasia in the Teleost Fish Medaka (Oryzias latipes)"],"prefix":"10.2108","volume":"41","author":[{"given":"Jos\u00e9","family":"Carranza","sequence":"first","affiliation":[{"name":"Laboratory of Reproductive Biology, Graduate School of Science, Nagoya University, Nagoya, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Yamada","sequence":"additional","affiliation":[{"name":"Laboratory of Reproductive Biology, Graduate School of Science, Nagoya University, Nagoya, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Sakae","sequence":"additional","affiliation":[{"name":"Division of Cancer Cell Biology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jongsung","family":"Noh","sequence":"additional","affiliation":[{"name":"Center for Advanced Biomolecular Recognition, Korea Institute of Science and Technology, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man Ho","family":"Choi","sequence":"additional","affiliation":[{"name":"Center for Advanced Biomolecular Recognition, Korea Institute of Science and Technology, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoru","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Laboratory of Reproductive Biology, Graduate School of Science, Nagoya University, Nagoya, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"848","reference":[{"key":"17","doi-asserted-by":"crossref","unstructured":"SD McCormick,  \"Amer Zool.\"  41, \"Endocrine control of osmoregulation in teleost fish.\" 781 (2001)","DOI":"10.1093\/icb\/41.4.781"},{"key":"37","doi-asserted-by":"crossref","unstructured":"PC White  and PW Speiser  \"Endocr Rev.\"  21, \"Congenital adrenal hyperplasia due to 21-hydroxylase deficiency.\" 245 (2000)","DOI":"10.1210\/edrv.21.3.0398"},{"key":"23","doi-asserted-by":"crossref","unstructured":"T Nishimura, K Yamada, C Fujimori, et al.  \"PLoS Genet.\"  14, \"Germ cells in the teleost fish medaka have an inherent feminizing effect.\" e1007259 (2018)","DOI":"10.1371\/journal.pgen.1007259"},{"key":"20","doi-asserted-by":"crossref","unstructured":"TP Mommsen, MM Vijayan, TW Moon,  \"Rev Fish Biol Fish.\"  9, \"Cortisol in teleosts: dynamics, mechanisms of action, and metabolic regulation.\" 211 (1999)","DOI":"10.1023\/A:1008924418720"},{"key":"24","doi-asserted-by":"crossref","unstructured":"I Quintero-Hunter, H Grier, M Muscato,  \"Biotech Histochem.\"  66, \"Enhancement of histological detail using metanil yellow as counterstain in periodic acid Schiff's hematoxylin staining of glycol methacrylate tissue sections.\" 169 (1991)","DOI":"10.3109\/10520299109109964"},{"key":"14","doi-asserted-by":"crossref","unstructured":"M Kikuchi, T Nishimura, S Ishishita, et al.  \"Proc Natl Acad Sci U S A.\"  117, \"foxl3, a sexual switch in germ cells, initiates two independent molecular pathways for commitment to oogenesis in medaka.\" 12174 (2020)","DOI":"10.1073\/pnas.1918556117"},{"key":"1","doi-asserted-by":"crossref","unstructured":"MC Adolfi, P Fischer, A Herpin, et al.  \"Mol Reprod Dev.\"  86, \"Increase of cortisol levels after temperature stress activates dmrt1a causing female-to-male sex reversal and reduced germ cell number in medaka.\" 1405 (2019)","DOI":"10.1002\/mrd.23177"},{"key":"2","doi-asserted-by":"crossref","unstructured":"A Aflatounian, MC Edwards, V Rodriguez Paris, et al.  \"J Endocrinol.\"  245, \"Androgen signaling pathway driving reproductive and metabolic phenotypes in a PCOS mouse model.\" 381 (2020)","DOI":"10.1530\/JOE-19-0530"},{"key":"3","doi-asserted-by":"crossref","unstructured":"RS Ara\u00fajo, BB Mendonca, AS Barbosa, et al.  \"J Clin Endocrinol Metab.\"  92, \"Microconversion between CYP21A2 and CYP21A1P promoter regions causes the non-classical form of 21-hydroxylase deficiency.\" 4028 (2007)","DOI":"10.1210\/jc.2006-2163"},{"key":"4","doi-asserted-by":"crossref","unstructured":"M Auer, A Nordenstr\u00f6m, S Lajic, et al.  \"Lancet.\"  401, \"Congenital adrenal hyperplasia.\" 227 (2023)","DOI":"10.1016\/S0140-6736(22)01330-7"},{"key":"5","doi-asserted-by":"crossref","unstructured":"X Cheng, X Chen, D Li, et al.  \"Gen Comp Endocrinol.\"  214, \"Effects of metronidazole on proopiomelanocortin a gene expression in zebrafish.\" 87 (2015)","DOI":"10.1016\/j.ygcen.2014.05.029"},{"key":"6","doi-asserted-by":"crossref","unstructured":"H Eachus, A Zaucker, JA Oakes, et al.  \"Endocrinology.\"  158, \"Genetic disruption of 21-hydroxylase in zebrafish causes interrenal hyperplasia.\" 4165 (2017)","DOI":"10.1210\/en.2017-00549"},{"key":"7","doi-asserted-by":"crossref","unstructured":"E Faught  and MM Vijayan  \"Fish Fish.\"  19, \"Maternal stress and fish reproduction: The role of cortisol revisited.\" 1016 (2018)","DOI":"10.1111\/faf.12309"},{"key":"8","doi-asserted-by":"crossref","unstructured":"HK Ghayee  and RJ Auchus  \"Rev Endocr Metab Disord.\"  8, \"Basic concepts and recent developments in human steroid hormone biosynthesis.\" 289 (2007)","DOI":"10.1007\/s11154-007-9052-2"},{"key":"9","doi-asserted-by":"crossref","unstructured":"H Gotoh, M Kusakabe, T Shiroishi, et al.  \"Endocrinology.\"  135, \"Survival of steroid 21-hydroxylase-deficient mice without endogenous corticosteroids after neonatal treatment and genetic rescue by transgenesis as a model system for treatment of congenital adrenal hyperplasia in humans.\" 1470 (1994)","DOI":"10.1210\/en.135.4.1470"},{"key":"10","doi-asserted-by":"crossref","unstructured":"S Han, T Baba, S Yanai, et al.  \"Andrology.\"  9, \"GC-MS-based metabolic signatures reveal comparative steroidogenic pathways between fetal and adult mouse testes.\" 400 (2020)","DOI":"10.1111\/andr.12893"},{"key":"11","doi-asserted-by":"crossref","unstructured":"O Hayasaka, Y Takeuchi, K Shiozaki, et al.  \"Sci Rep.\"  9, \"Green-light irradiation during sex differentiation induces female-to-male sex reversal in the medaka Oryzias latipes.\" 2383 (2019)","DOI":"10.1038\/s41598-019-38908-w"},{"key":"12","doi-asserted-by":"crossref","unstructured":"SG Hillier, PF Whitelaw, CD Smyth,  \"Mol Cell Endocrinol.\"  100, \"Follicular oestrogen synthesis: the \u201ctwo-cell, two-gonadotropin\u201d model revisited.\" 51 (1994)","DOI":"10.1016\/0303-7207(94)90278-X"},{"key":"13","doi-asserted-by":"crossref","unstructured":"SR Hornstein, T Tajima, G Eisenhofer, et al.  \"FASEB J.\"  13, \"Adrenomedullary function is severely impaired in 21-hydroxylase-deficient mice.\" 1185 (1999)","DOI":"10.1096\/fasebj.13.10.1185"},{"key":"15","doi-asserted-by":"crossref","unstructured":"C Lee, JH Kim, SJ Moon, et al.  \"J Steroid Biochem Mol Biol.\"  198, \"Selective LC-MRM\/SIM-MS based profiling of adrenal steroids reveals metabolic signatures of 17\u03b1-hydroxylase deficiency.\" 105615 (2020)","DOI":"10.1016\/j.jsbmb.2020.105615"},{"key":"16","doi-asserted-by":"crossref","unstructured":"X Liang, J Potter, S Kumar, et al.  \"J Biotechnology.\"  208, \"Rapid and highly efficient mammalian cell engineering via Cas9 protein transfection.\" 44 (2015)","DOI":"10.1016\/j.jbiotec.2015.04.024"},{"key":"18","doi-asserted-by":"crossref","unstructured":"DP Merke  and RJ Auchus  \"N Engl J Med.\"  383, \"Congenital adrenal hyperplasia due to 21-hydroxylase deficiency.\" 1248 (2020)","DOI":"10.1056\/NEJMra1909786"},{"key":"19","doi-asserted-by":"crossref","unstructured":"WL Miller,  \"Eur J Endocrinol.\"  179, \"Mechanisms in endocrinology: Rare defects in adrenal steroidogenesis.\" R125 (2018)","DOI":"10.1530\/EJE-18-0279"},{"key":"21","doi-asserted-by":"crossref","unstructured":"K Murata, M Kinoshita, K Naruse, et al.  \"Medaka: Biology, Management, and Experimental Protocols.\"  (2020)","DOI":"10.1002\/9781119575399"},{"key":"22","doi-asserted-by":"crossref","unstructured":"S Nakamura, D Kobayashi, Y Aoki, et al.  \"Dev Bio.\"  295, \"Identification and lineage tracing of two populations of somatic gonadal precursors in medaka embryos.\" 678 (2006)","DOI":"10.1016\/j.ydbio.2006.03.052"},{"key":"25","doi-asserted-by":"crossref","unstructured":"MR Royan, K Siddique, G Csucs, et al.  \"Front Endocrinol.\"  12, \"3D atlas of the pituitary gland of the model fish medaka (Oryzias latipes).\" 719843 (2021)","DOI":"10.3389\/fendo.2021.719843"},{"key":"26","doi-asserted-by":"crossref","unstructured":"N Reisch, AE Taylor, EF Nogueira, et al.  \"Proc Natl Acad Sci U S A.\"  116, \"Alternative pathway androgen biosynthesis and human fetal female virilization.\" 22294 (2019)","DOI":"10.1073\/pnas.1906623116"},{"key":"27","doi-asserted-by":"crossref","unstructured":"FG Riepe, S Tatzel, WG Sippell, et al.  \"Endocrinology.\"  146, \"Congenital adrenal hyperplasia: the molecular basis of 21-hydroxylase deficiency in H-2(aw18) mice.\" 2563 (2005)","DOI":"10.1210\/en.2004-1563"},{"key":"28","doi-asserted-by":"crossref","unstructured":"T Sakamoto, T Kozaka, A Takahashi, et al.  \"Aquaculture.\"  193, \"Medaka (Oryzias latipes) as a model for hypoosmoregulation of euryhaline fishes.\" 347 (2001)","DOI":"10.1016\/S0044-8486(00)00471-3"},{"key":"29","doi-asserted-by":"crossref","unstructured":"L Simonetti, CD Bruque, CS Fern\u00e1ndez, et al.  \"Hum Mutat.\"  39, \"CYP21A2 mutation update: Comprehensive analysis of databases and published genetic variants.\" 5 (2018)","DOI":"10.1002\/humu.23351"},{"key":"30","doi-asserted-by":"crossref","unstructured":"PW Speiser, W Arlt, RJ Auchus, et al.  \"J Clin Endocrinol Metab.\"  103, \"Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: An Endocrine Society clinical practice guideline.\" 4043 (2018)","DOI":"10.1210\/jc.2018-01865"},{"key":"31","doi-asserted-by":"crossref","unstructured":"M Stemmer, T Thumberger, M del Sol Keyer, et al.  \"PLOS ONE.\"  10, \"CCTop: an intuitive, flexible and reliable CRISPR\/Cas9 target prediction tool.\" e0124633 (2015)","DOI":"10.1371\/journal.pone.0124633"},{"key":"32","doi-asserted-by":"crossref","unstructured":"KH Storbeck, L Schiffer, E Baranowski, et al.  \"Endocr Rev.\"  40, \"Steroid metabolome analysis in disorders of adrenal steroid biosynthesis and metabolism.\" 1605 (2019)","DOI":"10.1210\/er.2018-00262"},{"key":"33","doi-asserted-by":"crossref","unstructured":"L Sun, W Xu, J He, et al.  \"Toxicol Appl Pharmacol.\"  248, \"In vivo alternative assessment of the chemicals that interfere with anterior pituitary POMC expression and interrenal steroidogenesis in POMC: EGFP transgenic zebrafish.\" 217 (2010)","DOI":"10.1016\/j.taap.2010.08.015"},{"key":"34","doi-asserted-by":"crossref","unstructured":"A Takahashi, S Kanda, T Abe, et al.  \"Endocrinology.\"  157, \"Evolution of the hypothalamic-pituitary-gonadal axis regulation in vertebrates revealed by knockout medaka.\" 3994 (2016)","DOI":"10.1210\/en.2016-1356"},{"key":"35","doi-asserted-by":"crossref","unstructured":"TT To, S Hahner, G Nica, et al.  \"Mol Endocrinol.\"  21, \"Pituitary-interrenal interaction in zebrafish interrenal organ development.\" 472 (2007)","DOI":"10.1210\/me.2006-0216"},{"key":"36","doi-asserted-by":"crossref","unstructured":"V Trayer, PP Hwang, P Prunet, et al.  \"Gen Comp Endocrinol.\"  194, \"Assessment of the role of cortisol and corticosteroid receptors in epidermal ionocyte development in the medaka (Oryzias latipes) embryos.\" 152 (2013)","DOI":"10.1016\/j.ygcen.2013.09.011"},{"key":"38","doi-asserted-by":"crossref","unstructured":"B Zhao, L Lei, N Kagawa, et al.  \"J Biol Chem.\"  287, \"Three-dimensional structure of steroid 21-hydroxylase (cytochrome P450 21A2) with two substrates reveals locations of disease-associated variants.\" 10613 (2012)","DOI":"10.1074\/jbc.M111.323501"},{"key":"39","doi-asserted-by":"crossref","unstructured":"LY Zhou, DS Wang, Y Shibata, et al.  \"Biochem Biophys Res Commun.\"  320, \"Characterization, expression and transcriptional regulation of P450c17-I and \u2013II in the medaka, Oryzias latipes\" 83 (2007)","DOI":"10.1016\/j.bbrc.2007.08.044"}],"container-title":["Zoological Science"],"original-title":[],"deposited":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T04:25:14Z","timestamp":1793420714000},"score":1,"resource":{"primary":{"URL":"https:\/\/bioone.org\/journals\/zoological-science\/volume-41\/issue-3\/zs230107\/Genetic-Disruption-of-cyp21a2-Leads-to-Systemic-Glucocorticoid-Deficiency-and\/10.2108\/zs230107.full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,8]]},"references-count":39,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,6,1]]}},"URL":"https:\/\/doi.org\/10.2108\/zs230107","relation":{},"ISSN":["0289-0003","2212-3830"],"issn-type":[{"value":"0289-0003","type":"print"},{"value":"2212-3830","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,8]]}}}