{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:30:02Z","timestamp":1792805402015,"version":"4.5.0"},"reference-count":94,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T00:00:00Z","timestamp":1726790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["320030-197725"],"award-info":[{"award-number":["320030-197725"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["POS_2020_1_0034"],"award-info":[{"award-number":["POS_2020_1_0034"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Education Department of the Basque Government (Spain)","award":["320030-197725"],"award-info":[{"award-number":["320030-197725"]}],"id":[{"id":"https:\/\/ror.org\/00pz2fp31","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Education Department of the Basque Government (Spain)","award":["POS_2020_1_0034"],"award-info":[{"award-number":["POS_2020_1_0034"]}],"id":[{"id":"https:\/\/ror.org\/00pz2fp31","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Steroidogenic factor 1 (SF-1) is a nuclear receptor that regulates steroidogenesis and reproductive development. NR5A1\/SF-1 variants are associated with a broad spectrum of phenotypes across individuals with disorders of sex development (DSDs). Oligogenic inheritance has been suggested as an explanation. SF-1 interacts with numerous partners. Here, we investigated a constellation of gene variants identified in a 46,XY severely undervirilized individual carrying an ACMG-categorized \u2018pathogenic\u2019 NR5A1\/SF-1 variant in comparison to the healthy carrier father. Candidate genes were revealed by whole exome sequencing, and pathogenicity was predicted by different in silico tools. We found variants in NR1H2 and INHA associated with steroidogenesis, sex development, and reproduction. The identified variants were tested in cell models. Novel SF-1 and NR1H2 binding sites in the AR and INHA gene promoters were found. Transactivation studies showed that wild-type NR5A1\/SF-1 regulates INHA and AR gene expression, while the NR5A1\/SF-1 variant had decreased transcriptional activity. NR1H2 was found to regulate AR gene transcription; however, the NR1H2 variant showed normal activity. This study expands the NR5A1\/SF-1 network of interacting partners, while not solving the exact interplay of different variants that might be involved in revealing the observed DSD phenotype. It also illustrates that understanding complex genetics in DSDs is challenging.<\/jats:p>","DOI":"10.3390\/ijms251810109","type":"journal-article","created":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T07:38:57Z","timestamp":1726817937000},"page":"10109","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["NR5A1\/SF-1 Collaborates with Inhibin \u03b1 and the Androgen Receptor"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2669-4170","authenticated-orcid":false,"given":"Rawda","family":"Naamneh Elzenaty","sequence":"first","affiliation":[{"name":"Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland"},{"name":"Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland"},{"name":"Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chrysanthi","family":"Kouri","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland"},{"name":"Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland"},{"name":"Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8943-1429","authenticated-orcid":false,"given":"Idoia","family":"Martinez de Lapiscina","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland"},{"name":"Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland"},{"name":"Biobizkaia Health Research Institute, Cruces University Hospital, University of the Basque, 48903 Barakaldo, Spain"},{"name":"CIBER de Diabetes y Enfermedades Metab\u00f3licas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Endo-ERN, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kay-Sara","family":"Sauter","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland"},{"name":"Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisca","family":"Moreno","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hospital Infantil La Fe, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4863-8201","authenticated-orcid":false,"given":"N\u00faria","family":"Camats-Tarruella","sequence":"additional","affiliation":[{"name":"Growth and Development Research Group, Vall d\u2019Hebron Research Institute, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christa E.","family":"Fl\u00fcck","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland"},{"name":"Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1210\/me.2009-0519","article-title":"Minireview: Steroidogenic factor 1: Its roles in differentiation, development, and disease","volume":"24","author":"Schimmer","year":"2010","journal-title":"Mol. 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