{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T17:40:12Z","timestamp":1789753212096,"version":"4.0.1"},"reference-count":53,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2020,11,13]],"date-time":"2020-11-13T00:00:00Z","timestamp":1605225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Basque Department of Education, Spain","award":["IT795-13"],"award-info":[{"award-number":["IT795-13"]}]},{"name":"personal research fellowship grant from the Spanish Pediatric Endocrine Society","award":["Personal Research grant to Idoia Martinez (first author)"],"award-info":[{"award-number":["Personal Research grant to Idoia Martinez (first author)"]}]},{"name":"European Reference Network on Rare Endocrine Conditions","award":["Endo-ERN Project ID No 739527"],"award-info":[{"award-number":["Endo-ERN Project ID No 739527"]}]},{"name":"Personal research fellowship grant of Science by Women from the Women for Africa foundation.","award":["Personal grant to Rana AA Mahmoud"],"award-info":[{"award-number":["Personal grant to Rana AA Mahmoud"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Variants of NR5A1 are often found in individuals with 46,XY disorders of sex development (DSD) and manifest with a very broad spectrum of clinical characteristics and variable sex hormone levels. Such complex phenotypic expression can be due to the inheritance of additional genetic hits in DSD-associated genes that modify sex determination, differentiation and organ function in patients with heterozygous NR5A1 variants. Here we describe the clinical, biochemical and genetic features of a series of seven patients harboring monoallelic variants in the NR5A1 gene. We tested the transactivation activity of novel NR5A1 variants. We additionally included six of these patients in a targeted diagnostic gene panel for DSD and identified a second genetic hit in known DSD-causing genes STAR, AMH and ZFPM2\/FOG2 in three individuals. Our study increases the number of NR5A1 variants related to 46,XY DSD and supports the hypothesis that a digenic mode of inheritance may contribute towards the broad spectrum of phenotypes observed in individuals with a heterozygous NR5A1 variation.<\/jats:p>","DOI":"10.3390\/ijms21228554","type":"journal-article","created":{"date-parts":[[2020,11,13]],"date-time":"2020-11-13T08:44:02Z","timestamp":1605257042000},"page":"8554","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Variants of STAR, AMH and ZFPM2\/FOG2 May Contribute towards the Broad Phenotype Observed in 46,XY DSD Patients with Heterozygous Variants of NR5A1"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8943-1429","authenticated-orcid":false,"given":"Idoia","family":"Mart\u00ednez de LaPiscina","sequence":"first","affiliation":[{"name":"Biocruces Bizkaia Health Research Institute, Cruces University Hospital, UPV\/EHU, CIBERER, CIBERDEM, ENDO-ERN. Plaza de Cruces 12, 48903 Barakaldo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5048-4651","authenticated-orcid":false,"given":"Rana AA","family":"Mahmoud","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Endocrinology Section, Ain Shams University, 38 Abbasia, Nour Mosque, El-Mohamady, Al Waili, Cairo 11591, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6912-324X","authenticated-orcid":false,"given":"Kay-Sara","family":"Sauter","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Department of BioMedical Research, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 15, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Esteva","sequence":"additional","affiliation":[{"name":"Endocrinology Section, Gender Identity Unit, Regional University Hospital of Malaga, Av. de Carlos Haya, s\/n, 29010 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milagros","family":"Alonso","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology Department, Ramon y Cajal University Hospital, Ctra. de Colmenar Viejo km. 9, 100, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"Costa","sequence":"additional","affiliation":[{"name":"Pediatric Department, Manises Hospital, Avda. Generalitat Valenciana 50, 46940 Manises, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Manuel","family":"Rial-Rodriguez","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology Department, Nuestra Se\u00f1ora de Candelaria University Hospital, Ctra general del Rosario 145, 38010 Santa Cruz de Tenerife, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amaia","family":"Rodr\u00edguez-Est\u00e9vez","sequence":"additional","affiliation":[{"name":"Biocruces Bizkaia Health Research Institute, Cruces University Hospital, UPV\/EHU, CIBERER, CIBERDEM, ENDO-ERN. Plaza de Cruces 12, 48903 Barakaldo, Spain"},{"name":"Pediatric Endocrinology Department, Cruces University Hospital, Plaza de Cruces 12, 48903 Barakaldo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amaia","family":"Vela","sequence":"additional","affiliation":[{"name":"Biocruces Bizkaia Health Research Institute, Cruces University Hospital, UPV\/EHU, CIBERER, CIBERDEM, ENDO-ERN. Plaza de Cruces 12, 48903 Barakaldo, Spain"},{"name":"Pediatric Endocrinology Department, Cruces University Hospital, Plaza de Cruces 12, 48903 Barakaldo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Castano","sequence":"additional","affiliation":[{"name":"Biocruces Bizkaia Health Research Institute, Cruces University Hospital, UPV\/EHU, CIBERER, CIBERDEM, ENDO-ERN. Plaza de Cruces 12, 48903 Barakaldo, Spain"},{"name":"Pediatric Endocrinology Department, Cruces University Hospital, Plaza de Cruces 12, 48903 Barakaldo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christa E.","family":"Fl\u00fcck","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Department of BioMedical Research, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 15, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/nrendo.2014.163","article-title":"Genetic regulation of mammalian gonad development","volume":"10","author":"Eggers","year":"2014","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Werner, R., M\u00f6nig, I., L\u00fcnstedt, R., W\u00fcnsch, L., Thorns, C., Reiz, B., Krause, A., Schwab, K.O., Binder, G., and Holterhus, P.-M. (2017). New NR5A1 mutations and phenotypic variations of gonadal dysgenesis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176720"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1038\/9629","article-title":"A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans","volume":"22","author":"Achermann","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/0092-8674(94)90211-9","article-title":"A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation","volume":"77","author":"Luo","year":"1994","journal-title":"Cell"},{"key":"ref_5","first-page":"58","article-title":"Mutation update for the NR5A1 gene involved in DSD and infertility","volume":"1","year":"2020","journal-title":"Hum. Mutat."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1002\/bdrc.21145","article-title":"Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals","volume":"108","author":"Domenice","year":"2016","journal-title":"Birth Defects Res. Part C Embryo Today"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1210\/jc.2011-3169","article-title":"Ten novel mutations in the NR5A1 gene cause disordered sex development in 46,XY and ovarian insufficiency in 46,XX individuals","volume":"97","author":"Camats","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1038\/s41431-018-0202-7","article-title":"Broad phenotypes in heterozygous NR5A1 46,XY patients with a disorder of sex development: An oligogenic origin?","volume":"26","author":"Camats","year":"2018","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1210\/jc.2013-3690","article-title":"Disorders of Sex Development (DSDs): An Update","volume":"99","author":"Ostrer","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1159\/000445983","article-title":"Identification of NR5A1 Mutations and Possible Digenic Inheritance in 46,XY Gonadal Dysgenesis","volume":"10","author":"Mazen","year":"2016","journal-title":"Sex. Dev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1186\/s13059-016-1105-y","article-title":"Disorders of sex development: Insights from targeted gene sequencing of a large international patient cohort","volume":"17","author":"Eggers","year":"2016","journal-title":"Genome Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1002\/humu.23354","article-title":"Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development","volume":"39","author":"Robevska","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1007\/s00439-018-1879-y","article-title":"Next-generation sequencing reveals genetic landscape in 46, XY disorders of sexual development patients with variable phenotypes","volume":"137","author":"Wang","year":"2018","journal-title":"Hum. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Camats, N., Fl\u00fcck, C.E., and Aud\u00ed, L. (2020). Oligogenic origin of differences of sex development in humans. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21051809"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7","DOI":"10.2174\/1874309901909010007","article-title":"Simple Virilizing Congenital Adrenal Hyperplasia: A case Report of Sudanese 46, XY DSD male with G293D variant in CYP21A2","volume":"9","author":"Ellaithi","year":"2019","journal-title":"Open Pediatr. Med. J."},{"key":"ref_16","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_17","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1530\/EJE-07-0113","article-title":"A novel mutation in the accessory DNA-binding domain of human steroidogenic factor 1 causes XY gonadal dysgenesis without adrenal insufficiency","volume":"157","author":"Reuter","year":"2007","journal-title":"Eur. J. Endocrinol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3657","DOI":"10.1093\/hmg\/ddu074","article-title":"Mutations in the FOG2\/ZFPM2 gene are associated with anomalies of human testis determination","volume":"23","author":"Bashamboo","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2855","DOI":"10.1210\/jc.2018-02178","article-title":"Functional Genetic Variation in the Anti-M\u00fcllerian Hormone Pathway in Women With Polycystic Ovary Syndrome","volume":"104","author":"Gorsic","year":"2019","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2868","DOI":"10.1210\/jc.2007-0024","article-title":"Heterozygous Mutation of Steroidogenic Factor-1 in 46,XY Subjects May Mimic Partial Androgen Insensitivity Syndrome","volume":"92","author":"Coutant","year":"2007","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_21","first-page":"9","article-title":"Phenotype and Molecular Characterizations of 30 Children From China With NR5A1 Mutations","volume":"30","author":"Song","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.ejmg.2009.02.009","article-title":"A unique 970kb microdeletion in 9q33.3, including the NR5A1 gene in a 46,XY female","volume":"52","author":"Boot","year":"2009","journal-title":"Eur. J. Med. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.jpag.2013.06.006","article-title":"A Novel Heterozygous Mutation in Steroidogenic Factor-1 in Pubertal Virilization of a 46,XY Female Adolescent","volume":"27","author":"Ceylaner","year":"2014","journal-title":"J. Pediatr. Adolesc. Gynecol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1530\/EJE-11-0944","article-title":"Testosterone production during puberty in two 46,XY patients with disorders of sex development and novel NR5A1 (SF-1) mutations","volume":"167","author":"Tantawy","year":"2012","journal-title":"Eur. J. Endocrinol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1159\/000505527","article-title":"Novel NR5A1 Pathogenic Variants Cause Phenotypic Heterogeneity in 46,XY Disorders of Sex Development","volume":"13","author":"Sudhakar","year":"2019","journal-title":"Sex. Dev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1056\/NEJMoa0806228","article-title":"Mutations in NR5A1 Associated with Ovarian Insufficiency","volume":"360","author":"Brauner","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.beem.2015.07.004","article-title":"DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease","volume":"29","author":"Suntharalingham","year":"2015","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Allali, S., Muller, J.-B., Brauner, R., Louren\u00e7o, D., Boudjenah, R., Karageorgou, V., Trivin, C., Lottmann, H., Lortat-Jacob, S., and Nihoul-F\u00e9k\u00e9t\u00e9, C. (2011). Mutation Analysis of NR5A1 Encoding Steroidogenic Factor 1 in 77 Patients with 46, XY Disorders of Sex Development (DSD) Including Hypospadias. Gromoll J, editor. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0024117"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1016\/j.fertnstert.2018.02.123","article-title":"Mutational and functional studies on NR5A1 gene in 46,XY disorders of sex development: Identification of six novel loss of function mutations","volume":"109","author":"Rocca","year":"2018","journal-title":"Fertil. Steril."},{"key":"ref_30","first-page":"1","article-title":"Follow-up of two similar patients with Steroidogenic Factor-1 (SF-1\/ NR5A1) variants in two different eras","volume":"91","author":"Gaisl","year":"2019","journal-title":"Horm. Res. Paediatr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1159\/000354990","article-title":"NR5A1 Gene Mutations: Clinical, Endocrine and Genetic Features in Two Girls with 46,XY Disorder of Sex Development","volume":"81","author":"Bertelloni","year":"2014","journal-title":"Horm. Res. Paediatr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7193","DOI":"10.1128\/MCB.22.20.7193-7203.2002","article-title":"Phosphorylation and Intramolecular Stabilization of the Ligand Binding Domain in the Nuclear Receptor Steroidogenic Factor 1","volume":"22","author":"Desclozeaux","year":"2002","journal-title":"Mol. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1159\/000152036","article-title":"Steroidogenic Factor-1 (SF-1, Ad4BP, NR5A1) and Disorders of Testis Development","volume":"2","author":"Lin","year":"2008","journal-title":"Sex. Dev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1507\/endocrj.EJ14-0340","article-title":"Fertility preservation in a family with a novel NR5A1 mutation","volume":"3","author":"Yagi","year":"2015","journal-title":"Endocr. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/978-1-4419-8002-1_16","article-title":"Phenotypic variation of SF1 gene mutations","volume":"707","author":"Philibert","year":"2011","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Fl\u00fcck, C.E., Aud\u00ed, L., Fern\u00e1ndez-Cancio, M., Sauter, K.-S., Martinez de LaPiscina, I., Casta\u00f1o, L., Esteva, I., and Camats, N. (2019). Broad Phenotypes of Disorders\/Differences of Sex Development in MAMLD1 Patients Through Oligogenic Disease. Front. Genet., 10.","DOI":"10.3389\/fgene.2019.00746"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kolesinska, Z., Acierno, J., Ahmed, S.F., Xu, C., Kapczuk, K., Skorczyk-Werner, A., Mikos, H., Rojek, A., Massouras, A., and Krawczynski, M.A. (2018). Integrating clinical and genetic approaches in the diagnosis of 46,XY disorders of sex development. Endocr. Connect., 1480\u20131490.","DOI":"10.1530\/EC-18-0472"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1093\/humrep\/deu364","article-title":"Molecular basis of non-syndromic hypospadias: Systematic mutation screening and genome-wide copy-number analysis of 62 patients","volume":"30","author":"Kon","year":"2015","journal-title":"Hum. Reprod."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"R99","DOI":"10.1530\/EJE-17-0128","article-title":"Mechanisms in Endocrinology: Update on pathogenesis of primary adrenal insufficiency: Beyond steroid enzyme deficiency and autoimmune adrenal destruction","volume":"177","year":"2017","journal-title":"Eur. J. Endocrinol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/0092-8674(94)90050-7","article-title":"Nuclear receptor steroidogenic factor 1 regulates the m\u00fcllerian inhibiting substance gene: A link to the sex determination cascade","volume":"77","author":"Shen","year":"1994","journal-title":"Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1038\/nature06944","article-title":"Erratum: Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer","volume":"453","author":"Sekido","year":"2008","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Moses, M.M., and Behringer, R.R. (2019). A gene regulatory network for M\u00fcllerian duct regression. Skinner, M., editor. Environ. Epigenet., 5.","DOI":"10.1093\/eep\/dvz017"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"14994","DOI":"10.1073\/pnas.0701677104","article-title":"Correct dosage of Fog2 and Gata4 transcription factors is critical for fetal testis development in mice","volume":"104","author":"Bouma","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1210\/en.2019-00047","article-title":"In Vivo Ablation of the Conserved GATA-Binding Motif in the Amh Promoter Impairs Amh Expression in the Male Mouse","volume":"160","author":"Bouchard","year":"2019","journal-title":"Endocrinology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.ydbio.2007.04.040","article-title":"The regulation of Sox9 gene expression by the GATA4\/FOG2 transcriptional complex in dominant XX sex reversal mouse models","volume":"307","author":"Manuylov","year":"2007","journal-title":"Dev. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4627","DOI":"10.1242\/dev.129.19.4627","article-title":"Gonadal differentiation, sex determination and normal Sry expression in mice require direct interaction between transcription partners GATA4 and FOG2","volume":"129","author":"Tevosian","year":"2002","journal-title":"Development"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1002\/humu.10261","article-title":"Mutations of ZFPM2\/FOG2 gene in sporadic cases of tetralogy of Fallot","volume":"22","author":"Pizzuti","year":"2003","journal-title":"Hum. Mutat."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Bergen, J.A., Robevska, G., Eggers, S., Riedl, S., Grover, S.R., Bergman, P.B., Kimber, C., Jiwane, A., Khan, S., and Krausz, C. (2020). Analysis of variants in GATA4 and FOG2 \/ ZFPM2 demonstrates benign contribution to 46,XY disorders of sex development. Mol. Genet. Genom. Med., 8.","DOI":"10.1002\/mgg3.1095"},{"key":"ref_49","first-page":"1236","article-title":"Modeling Congenital Adrenal Hyperplasia and Testing Interventions for Adrenal Insufficiency Using Donor-Specific Reprogrammed Cells","volume":"5","author":"Balyura","year":"2018","journal-title":"Cell Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"498","DOI":"10.3389\/fgene.2018.00498","article-title":"human gonadal cell model from induced pluripotent stem cells","volume":"9","author":"Eid","year":"2018","journal-title":"Front. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"23274","DOI":"10.1073\/pnas.1908207116","article-title":"Directing differentiation of human induced pluripotent stem cells toward androgen-producing Leydig cells rather than adrenal cells","volume":"46","author":"Li","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"ref_52","first-page":"1","article-title":"GATA4 variants in individuals with a 46,XY Disorder of Sex Development (DSD) may or may not be associated with cardiac defects depending on second hits in other DSD genes","volume":"9","author":"Riedl","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1210\/me.2003-0342","article-title":"GATA-4 and GATA-6 Modulate Tissue-Specific Transcription of the Human Gene for P450c17 by Direct Interaction with Sp1","volume":"18","author":"Miller","year":"2004","journal-title":"Mol. Endocrinol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/22\/8554\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:32:53Z","timestamp":1760178773000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/22\/8554"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,13]]},"references-count":53,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["ijms21228554"],"URL":"https:\/\/doi.org\/10.3390\/ijms21228554","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,13]]}}}