{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T08:09:26Z","timestamp":1780387766217,"version":"3.54.1"},"reference-count":12,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T00:00:00Z","timestamp":1777852800000},"content-version":"vor","delay-in-days":3,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Bursa Uludag University"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Reprod. Sci."],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    46,XY disorders of sexual development (46,XY DSD) are conditions characterized by deviations from typical male sex development, which encompasses a broad spectrum of clinical features such as hypospadias, decreased sperm production, dysgenetic testes, bifid scrotum, and the presence of a mature uterus and fallopian tubes. The\n                    <jats:italic>WWOX<\/jats:italic>\n                    gene, which has been implicated in various cancers, is also thought to play a role in sex development, although its involvement in 46,XY DSD remains poorly understood. This study aimed to investigate the\n                    <jats:italic>WWOX<\/jats:italic>\n                    gene in a patient presenting with hypospadias. A 7-month-old male with a history of in-vitro fertilization pregnancy due to male factor and premature birth was referred to our clinic for hypospadias and undescended testicles. The physical examination showed scrotal hypospadias and significant chordee. Chromosome analysis was 46,XY, and the sex-determining region Y protein was positive. Using DNA sequence analysis and protein expression studies, the p.Ala141Thr variant in the\n                    <jats:italic>WWOX<\/jats:italic>\n                    gene was identified. DNA sequencing analysis revealed that the patient is homozygous for this variant, with the father being homozygous (having an infertility history but no physical examination) and the mother heterozygous for the same mutation. Western blot analysis revealed significantly reduced WWOX protein levels in both the proband and father compared to the healthy controls, indicating that the variant impaired protein expression. These findings were consistent with the results from in-silico analyses, which predicted that the p.Ala141Thr substitution disrupts the secondary structure of the WWOX protein, suggesting a functional impact on its activity.\n                  <\/jats:p>","DOI":"10.1007\/s43032-026-02112-9","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T17:19:24Z","timestamp":1777915164000},"page":"1020-1025","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Role of WWOX Gene Variant in Hypospadias and 46,XY Disorders of Sexual Development"],"prefix":"10.1007","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5657-4260","authenticated-orcid":false,"given":"Yasemin","family":"Denkboy Ongen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Havva","family":"Tezcan-Unlu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ufuk","family":"Unal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ecem","family":"Efendi-Erdem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gulsah","family":"Cecener","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erdal","family":"Eren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"issue":"3","key":"2112_CR1","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1016\/j.jpurol.2022.11.023","volume":"19","author":"P Srivastava","year":"2023","unstructured":"Srivastava P, Tenney J, Lodish M, Slavotinek A, Baskin L. Utility of genetic work-up for 46, XY patients with severe hypospadias. J Pediatr Urol. 2023;19(3):261\u201372. https:\/\/doi.org\/10.1016\/j.jpurol.2022.11.023.","journal-title":"J Pediatr Urol"},{"issue":"10","key":"2112_CR2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0024117","volume":"6","author":"S Allali","year":"2011","unstructured":"Allali S, Muller JB, Brauner R, et al. Mutation analysis of NR5A1 encoding steroidogenic factor 1 in 77 patients with 46, XY disorders of sex development (DSD) including hypospadias. PLoS ONE. 2011;6(10):e24117. https:\/\/doi.org\/10.1371\/journal.pone.0024117.","journal-title":"PLoS ONE"},{"issue":"5","key":"2112_CR3","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1111\/andr.13708","volume":"13","author":"F Idris","year":"2025","unstructured":"Idris F, Sinclair AH, Ayers KL. Genomic technologies and the diagnosis of 46, XY differences of sex development. Andrology. 2025;13(5):1025\u201343. https:\/\/doi.org\/10.1111\/andr.13708.","journal-title":"Andrology"},{"issue":"2","key":"2112_CR4","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1002\/jcp.21099","volume":"212","author":"RI Aqeilan","year":"2007","unstructured":"Aqeilan RI, Croce CM. WWOX in biological control and tumorigenesis. J Cell Physiol. 2007;212(2):307\u201310. https:\/\/doi.org\/10.1002\/jcp.21099.","journal-title":"J Cell Physiol"},{"issue":"3","key":"2112_CR5","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1177\/1535370214561590","volume":"240","author":"MS Schrock","year":"2015","unstructured":"Schrock MS, Huebner K. WWOX: a fragile tumor suppressor. Exp Biol Med (Maywood). 2015;240(3):296\u2013304. https:\/\/doi.org\/10.1177\/1535370214561590.","journal-title":"Exp Biol Med (Maywood)"},{"issue":"4","key":"2112_CR6","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1369\/0022155421991629","volume":"69","author":"MAA Mahmud","year":"2021","unstructured":"Mahmud MAA, Noguchi M, Domon A, Tochigi Y, Katayama K, Suzuki H. Cellular expression and subcellular localization of wwox protein during testicular development and spermatogenesis in rats. J Histochem Cytochem. 2021;69(4):257\u201370. https:\/\/doi.org\/10.1369\/0022155421991629.","journal-title":"J Histochem Cytochem"},{"issue":"3","key":"2112_CR7","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1038\/ejhg.2011.204","volume":"20","author":"S White","year":"2012","unstructured":"White S, Hewitt J, Turbitt E, et al. A multi-exon deletion within WWOX is associated with a 46,XY disorder of sex development. Eur J Hum Genet. 2012;20(3):348\u201351. https:\/\/doi.org\/10.1038\/ejhg.2011.204.","journal-title":"Eur J Hum Genet"},{"issue":"1","key":"2112_CR8","doi-asserted-by":"publisher","DOI":"10.1186\/s13293-024-00644-w","volume":"15","author":"J Wu","year":"2024","unstructured":"Wu J, Tan S, Feng Z, et al. Whole-genome de novo sequencing reveals genomic variants associated with differences of sex development in SRY negative pigs. Biol Sex Differ. 2024;15(1):68. https:\/\/doi.org\/10.1186\/s13293-024-00644-w.","journal-title":"Biol Sex Differ"},{"issue":"4","key":"2112_CR9","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1159\/000524956","volume":"16","author":"H Fabbri-Scallet","year":"2022","unstructured":"Fabbri-Scallet H, Werner R, Guaragna MS, et al. Can non-coding NR5A1 gene variants explain phenotypes of disorders of sex development? Sex Dev. 2022;16(4):252\u201360. https:\/\/doi.org\/10.1159\/000524956.","journal-title":"Sex Dev"},{"issue":"6","key":"2112_CR10","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.1038\/s41436-018-0339-3","volume":"21","author":"J Piard","year":"2019","unstructured":"Piard J, Hawkes L, Milh M, et al. The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature. Genet Med. 2019;21(6):1308\u201318. https:\/\/doi.org\/10.1038\/s41436-018-0339-3.","journal-title":"Genet Med"},{"key":"2112_CR11","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.mce.2017.01.037","volume":"444","author":"JH Kim","year":"2017","unstructured":"Kim JH, Kang E, Heo SH, et al. Diagnostic yield of targeted gene panel sequencing to identify the genetic etiology of disorders of sex development. Mol Cell Endocrinol. 2017;444:19\u201325. https:\/\/doi.org\/10.1016\/j.mce.2017.01.037.","journal-title":"Mol Cell Endocrinol"},{"issue":"3","key":"2112_CR12","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1038\/ejhg.2011.204","volume":"20","author":"S White","year":"2012","unstructured":"White S, Hewitt J, Turbitt E, et al. A multi-exon deletion within WWOX is associated with a 46,XY disorder of sex development. Eur J Hum Genet. 2012;20(3):348\u201351. https:\/\/doi.org\/10.1038\/ejhg.2011.204.","journal-title":"Eur J Hum Genet"}],"container-title":["Reproductive Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s43032-026-02112-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s43032-026-02112-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s43032-026-02112-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T07:36:20Z","timestamp":1780385780000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s43032-026-02112-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5]]},"references-count":12,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["2112"],"URL":"https:\/\/doi.org\/10.1007\/s43032-026-02112-9","relation":{},"ISSN":["1933-7191","1933-7205"],"issn-type":[{"value":"1933-7191","type":"print"},{"value":"1933-7205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5]]},"assertion":[{"value":"10 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This research was conducted in accordance with the principles of the Declaration of Helsinki and received approval from the University Ethics Committee (Approval No: 2011-KAEK-26). All procedures were performed in compliance with the approved ethical standards.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"Informed consent is taken from the patient for participation and publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"Informed consent is taken from the patient for participation and publication.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"The authors declare that they have no conflicts of interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}]}}