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Characterization of 35 Novel NR5A1/SF-1 Variants Identified in Individuals with Atypical Sexual Development: The SF1next Study

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dc.authorscopusid57700676900
dc.authorscopusid57194740491
dc.authorscopusid58145402800
dc.authorscopusid12142676700
dc.authorscopusid56785456600
dc.authorscopusid7006811260
dc.authorscopusid56966682400
dc.contributor.authorNaamneh-Elzenaty, R.
dc.contributor.authorde LaPiscina, I.
dc.contributor.authorKouri, C.
dc.contributor.authorSauter, K.-S.
dc.contributor.authorSommer, G.
dc.contributor.authorCastaño, L.
dc.contributor.authorFlück, C.E.
dc.date.accessioned2025-12-11T00:34:36Z
dc.date.issued2025
dc.departmentOndokuz Mayıs Üniversitesien_US
dc.department-temp[Naamneh-Elzenaty] Rawda, Department of Pediatrics, University Hospital Bern, Bern, BE, Switzerland, Department of Biomedical Research, University of Bern, Bern, BE, Switzerland, Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, BE, Switzerland; [de LaPiscina] Idoia Martinez, Department of Pediatrics, University Hospital Bern, Bern, BE, Switzerland, Department of Biomedical Research, University of Bern, Bern, BE, Switzerland, Research into the Genetics and Control of Diabetes and other Endocrine Disorders, Osakidetza, Cruces University Hospital, Baracaldo, Biscay, Spain, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Madrid, Spain, Department of Rare Endocrine Conditions, Endo-ERN, Amsterdam, Netherlands; [Kouri] Chrysanthi, Department of Pediatrics, University Hospital Bern, Bern, BE, Switzerland, Department of Biomedical Research, University of Bern, Bern, BE, Switzerland, Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, BE, Switzerland; [Sauter] Kay Sara, Department of Pediatrics, University Hospital Bern, Bern, BE, Switzerland, Department of Biomedical Research, University of Bern, Bern, BE, Switzerland; [Sommer] Grit, Department of Pediatrics, University Hospital Bern, Bern, BE, Switzerland, Department of Biomedical Research, University of Bern, Bern, BE, Switzerland; [Castaño] Luis Antonio, Research into the Genetics and Control of Diabetes and other Endocrine Disorders, Osakidetza, Cruces University Hospital, Baracaldo, Biscay, Spain, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Madrid, Spain, Department of Rare Endocrine Conditions, Endo-ERN, Amsterdam, Netherlands, Department of Pediatric Endocrinology, Osakidetza, Cruces University Hospital, Baracaldo, Biscay, Spain, Department of Pediatrics, Universidad del Pais Vasco, Leioa, Biscay, Spain; [Flück] Christa E., Department of Pediatrics, University Hospital Bern, Bern, BE, Switzerland, Department of Biomedical Research, University of Bern, Bern, BE, Switzerland; [Abali] Saygin, School of Medicine, Acıbadem Mehmet Ali Aydınlar Üniversitesi, Istanbul, Turkey; [Yavas-Abali] Zehra, Department of Pediatric Endocrinology and Diabetes, Marmara Üniversitesi, Istanbul, Turkey; [Ahmed] F., Dentistry & Nursing, School of Medicine, Dentistry & Nursing, Glasgow, Scotland, United Kingdom, University of Glasgow, Glasgow, Scotland, United Kingdom; [Akin] Leyla, Department of Pediatric Endocrinology and Diabetes, Ondokuz Mayis Üniversitesi, Samsun, Turkey; [Almaraz] Maricruz C., Department of Endocrinology and Nutrition, Hospital Regional Universitario Carlos Haya, Malaga, Malaga, Spain; [Audí] L., Growth and Development Research Unit, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Madrid, Spain; [Aydin] Murat, Department of Pediatric Endocrinology and Diabetes, Ondokuz Mayis Üniversitesi, Samsun, Turkey; [Balsamo] Antonio, Alma Mater Studiorum, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, BO, Italy; [Baronio] Federico, Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, BO, Italy; [Bryce] Jillian, University of Glasgow, Glasgow, Scotland, United Kingdom; [Busiah] Kanetee, Diabetology and Obesity Unit, Centre Hospitalier Universitaire Vaudois, Lausanne, VD, Switzerland; [Caimarí] María, Hospital Universitario Son Espases, Palma, Balearic Islands, Spain; [CamatsTarruella] N., Growth and Development Research Unit, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Madrid, Spain; [Campos-Martorell] Ariadna, Hospital Universitari Vall d'Hebron, Barcelona, Barcelona, Spain; [Casterás] Anna, Department of Endocrinology, Hospital Universitari Vall d'Hebron, Barcelona, Barcelona, Spain; [Çetinkaya] Semra Çaǧlar, Clinic of Pediatric Endocrinology, University of Health Sciences, Istanbul, Turkey; [Chan] Yeeming, Division of Endocrinology, Boston Children's Hospital, Boston, MA, United States, Department of Pediatrics, Harvard Medical School, Boston, MA, United States; [Claahsen – van der Grinten] Hedi L., Department of Paediatric Endocrinology, Radboud University Medical Center, Nijmegen, Gelderland, Netherlands; [Costa] Ines, Department of Pediatrics, Hospital de Manises, Manises, Valencia, Spain; [Cools] Martine C., Department of Internal Medicine and Paediatrics, Universitair Ziekenhuis Gent, Ghent, VOV, Belgium; [Darendeli̇Ler] Feyza F., Pediatric Endocrinology Unit, İstanbul Tıp Fakültesi, Istanbul, Turkey; [Davies] Justin H., Southampton General Hospital, Southampton, Hampshire, United Kingdom; [Esteva] Isabel, Department of Endocrinology, Hospital Regional Universitario Carlos Haya, Malaga, Malaga, Spain; [Fabbri-Scallet] Helena Campos, Laboratory of Human Genetics, Universidade Estadual de Campinas, Campinas, SP, Brazil; [Finlayson] Courtney Anne, Division of Endocrinology, Children's Memorial Hospital, Chicago, IL, United States; [García] Emilio, Hospital Universitario Virgen del Rocío, Sevilla, Seville, Spain; [García-Cuartero] Beatriz, Department of Pediatric Endocrinology, Hospital Universitario Ramón y Cajal, Madrid, Madrid, Spain; [German] Alina, Emek Medical Center, Afula, Israel, Technion - Israel Institute of Technology, Haifa, Israel; [Globa] Evgenia V., State Non-Commercial Enterprise «Ukrainian Scientific and Practice Center of EndocrineSurgery, Transplantation of Endocrine Organs and Tissues under MoH of Ukraine», Kyiv, Ukraine; [Guerra] Gil, Department of Pediatrics, Universidade Estadual de Campinas, Campinas, SP, Brazil; [Guerrero] Julio, Hospital Materno-Infantil, Madrid, Madrid, Spain; [Güran] Tülay, Department of Pediatric Endocrinology and Diabetes, Marmara Üniversitesi, Istanbul, Turkey; [Hannema] S. E., Department of Pediatrics, Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands, Department of Pediatric Endocrinology, Erasmus MC Sophia Children’s Hospital, Rotterdam, Zuid-Holland, Netherlands; [Hiort] Olaf, Department of Pediatrics, Universität zu Lübeck, Lubeck, Schleswig-Holstein, Germany; [Hirsch] Josephine A., Division of Urology, Children's Memorial Hospital, Chicago, IL, United States; [Hughes] Ieuan A., Department of Paediatrics, Cambridge, Cambridgeshire, United Kingdom; [Janner] Marco, Pediatric Endocrinology, University Hospital Bern, Bern, BE, Switzerland; [Kolesińska] Zofia, Department of Pediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences, Poznan, Wielkopolska Province, Poland; [Lachlan] Katherine L., Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, Hampshire, United Kingdom; [L'Allemand] Dagmar, Department of Endocrinology, Children's Hospital of Eastern Switzerland, St Gallen, Switzerland; [Malíková] Jana Krenek, Department of Pediatrics, Fakultní Nemocnice v Motole, Prague, Czech Republic; [Lang-Muritano] Mariarosaria R., Children's Research Centre, Kinderspital Zürich, Zurich, Switzerland; [Lucas-Herald] Angela Katrina, Dentistry & Nursing, School of Medicine, Dentistry & Nursing, Glasgow, Scotland, United Kingdom; [Mammadova] Jamala, DSD-Translational Research Network, Ann Arbor, MI, United States; [McElreavey] Ken D., Human Developmental Genetics, Institut Pasteur, Paris, Paris, Ile-de-France, France; [Mericq] Verónica, Institute of Maternal and Child Research, Universidad de Chile, Santiago, RM, Chile; [Mönig] Isabel, Department of Pediatrics, Universität zu Lübeck, Lubeck, Schleswig-Holstein, Germany; [Moreno] Francisca, Hospital Infantil La Fe, Valencia, Valencia, Spain; [Niedziela] Marek, Department of Pediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences, Poznan, Wielkopolska Province, Poland; [Nordenström] Anna, Department of Women's and Children's Health, Karolinska Universitetssjukhuset, Stockholm, Stockholms, Sweden; [Orman] Burçe, Clinic of Pediatric Endocrinology, Dr. Sami Ulus Obstetrics and Gynecology and Pediatrics Training and Research Hospital, Ankara, Turkey, University of Health Sciences, Istanbul, Turkey; [Poyrazoǧlu] Şükran, Pediatric Endocrinology Unit, İstanbul Tıp Fakültesi, Istanbul, Turkey; [Rial] José Manuel, Pediatric Endocrinology Department, Hospitem Rambla, Santa Cruz, Spain; [Rutter] Meilan M., DSD-Translational Research Network, Ann Arbor, MI, United States, Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati, OH, United States; [Rodríguez] Amaia, Biocruces Bizkaia Instituto de Investigación Sanitaria, Baracaldo, Biscay, Spain; [Schafer-Kalkhoff] Tara, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States; [Seneviratne] Sumudu Nimali, Department of Pediatrics, University of Colombo, Colombo, Sri Lanka; [Sredkova-Ruskova] Maria, Department of Clinical Genetics, Medical University of Sofia, Sofia, Bulgaria; [Tack] L. J.W., Department of Internal Medicine and Paediatrics, Universitair Ziekenhuis Gent, Ghent, VOV, Belgium; [Tadokoro-Cuccaro] Rieko, Department of Paediatrics, Cambridge, Cambridgeshire, United Kingdom; [Thankamony] Ajay, Department of Pediatrics, Addenbrooke's Hospital, Cambridge, Cambridgeshire, United Kingdom; [Tome] Monica, Department of Endocrinology and Nutrition, Hospital Regional Universitario Carlos Haya, Malaga, Malaga, Spain; [Vela] Amaia, Biocruces Bizkaia Instituto de Investigación Sanitaria, Baracaldo, Biscay, Spain; [Wasniewska] Malgorzata Gabriela, Department of Human Pathology of Adulthood and Childhood, Università degli Studi di Messina, Messina, ME, Italy; [Zangen] David Haim, Faculty of Medicine, Jerusalem, Israel, Pediatric Endocrinology Unit, Hadassah University Medical Centre, Jerusalem, Israel; [Zelinska] Nataliya B., State Non-Commercial Enterprise «Ukrainian Scientific and Practice Center of EndocrineSurgery, Transplantation of Endocrine Organs and Tissues under MoH of Ukraine», Kyiv, Ukraine; [Mührer] Julia, Children's Research Centre, Kinderspital Zürich, Zurich, Switzerlanden_US
dc.description.abstractContext: Steroidogenic factor 1 (NR5A1/SF-1) is a nuclear receptor that regulates sex development, steroidogenesis, and reproduction. Genetic variants in NR5A1/SF-1 are common among differences of sex development (DSD) and associate with a wide range of phenotypes, but their pathogenic mechanisms remain unclear. Objective: Novel, likely disease-causing NR5A1/SF-1 variants from the SF1next cohort of individuals with DSD were characterized to elucidate their pathogenic effect. Methods: Different in silico tools were used to predict the impact of novel NR5A1/SF-1 variants on protein function. An extensive literature review was conducted to compare and select the best functional studies for testing the pathogenic effect of the variants in a classic cell culture model. The missense NR5A1/SF-1 variants were tested on the promoter luciferase reporter vector -152CYP11A1-pGL3 in HEK293T cells and assessed for their cytoplasmic/nuclear localization by Western blot. Results: Thirty-five novel NR5A1/SF-1 variants were identified in the SF1next cohort. Seventeen missense NR5A1/SF-1 variants were functionally tested. Transactivation assays showed reduced activity for 40% of the variants located in the DNA binding domain and variable activity for variants located elsewhere. Translocation assessment revealed 3 variants (3/17) with affected nuclear translocation. No clear genotype-phenotype, structure-function correlation was found. Conclusion: Genetic analyses and functional assays do not explain the observed wide phenotype of individuals with these novel NR5A1/SF-1 variants. In 9 individuals, additional likely disease-causing variants in other genes were found, strengthening the hypothesis that the broad phenotype of DSD associated with NR5A1/SF-1 variants may be caused by an oligogenic mechanism. © 2024 The Author(s). Published by Oxford University Press on behalf of the Endocrine Society.en_US
dc.identifier.doi10.1210/clinem/dgae251
dc.identifier.endpagee693en_US
dc.identifier.issn1945-7197
dc.identifier.issue3en_US
dc.identifier.pmid38623954
dc.identifier.scopus2-s2.0-85194255083
dc.identifier.scopusqualityQ1
dc.identifier.startpagee675en_US
dc.identifier.urihttps://doi.org/10.1210/clinem/dgae251
dc.identifier.urihttps://hdl.handle.net/20.500.12712/37637
dc.identifier.volume110en_US
dc.identifier.wosqualityQ1
dc.language.isoenen_US
dc.publisherEndocrine Societyen_US
dc.relation.ispartofJournal of Clinical Endocrinology & Metabolismen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectBroad Phenotypeen_US
dc.subjectDifferences of Sex Development (DSD)en_US
dc.subjectGenotype-Phenotype Correlationen_US
dc.subjectSteroidogenic Factor 1 (SF-1/NR5A1)en_US
dc.titleCharacterization of 35 Novel NR5A1/SF-1 Variants Identified in Individuals with Atypical Sexual Development: The SF1next Studyen_US
dc.typeArticleen_US
dspace.entity.typePublication

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